Tricyclic indole compounds having affinity for serotonin receptor

ABSTRACT

Having an affinity against serotonine receptors, compound (I) shown below is useful as a therapeutic agent against various kinds of diseases of central nervous systems; 
                 
 
(wherein R 1  is hydrogen; R 2  is hydrogen or lower alkyl; R 3  is hydrogen, —COOR 12  and so on; R 4  is hydrogen, lower alkyl and so on, or R 3  and R 4  taken together may form ═O or ═S; R 5  is hydrogen, or R 3  and R 5  taken together may form a bond; R 6  is hydrogen, —COOR 24  and so on; R 7  is hydrogen, halogen, lower alkyl and so on; R 8  is hydrogen, lower alkyl, cycloalkyl and so on; R 9 , R 10  and R 11  are each independently hydrogen, halogen, lower alkyl and so on).

This application is a U.S. national stage of International ApplicationNo. PCT/JP01/08049 filed Sep. 17, 2001.

1. Techinical Field

The present invention is related to tricyclic indole compounds. Havingan affinity against serotonin receptors, the present compounds areuseful as medicines, for example, a therapeutic agent for diseases ofcentral nervous system thereof and useful as synthetic intermediatesthereof.

2. Background Art

Serotonin (5-hydroxytryptamine) is one of amines, which exists in livingbody, and has a lot of physiological activities. For example, serotoninis located in granule cell of intestinal basal and promotes the movementof the intestinal tract. And also, on an occasion of bleeding, serotoninis released from platelets into blood and concerned with hemostasis bycontracting blood capillary. Apart from this, serotonin works as aneurotransmitter in brain and takes part in modulating mental action,limit of pain, body-temperature and sleep-awakening cycle thereof,through serotonin receptors [Physiol. Rev. 72(1992) 165-229].

It has been reported that serotonin receptors are classified mainly toseven families and by including their subtypes, at least 14 kinds ofreceptors have been identified until now. Each receptor is reported tobe concerned with various kinds of physiological functions and diseases[Pharmacol. Rev. 46(1994) 157-203]. Displaying to have agonistic orantagonistic activities, an agent having a binding affinity againstserotonin receptors, is expected to be a therapeutic or prophylacticmedicament. [Pharmacol.Rev. 43(1991) 509-525].

Among them, 5-HT_(5A), 5-HT_(5B), 5-HT₆, and 5-HT₇ are receptors whichhave been recently identified and cloned [FEBS Lett. 355(1994) 242-6,FEBS Lett. 333(1993) 25-31, J. Neurochem. 66(1996) 47-56, Neuron,11(1993) 449-458] and there is few report about the selective agonistand antagonist. Each of these receptors has already been known to belocated mainly in central nervous system. For example, it has beenreported that 5-HT_(5A) and 5-HT_(5B) receptors are located inhippocampus and cerebral cortex, which are profoundly concerned withlearning and memory [FEBS Lett. 355 (1994) 242-6, FEBS Lett. 333 (1993)25-31], 5-HT₆ receptor is located in corpus striatum, which is concernedwith motor function [J. Neurochem. 66 (1996) 47-56], and 5-HT₇ receptoris located in suprachiasmatic nucleus, which is concerned with mammalianbiological clock [Neuron, 11(1993) 449-458]. Therefore, there is apossibility for the selective agonist or antagonist against the receptorto be a therapeutic agent for dementia, Parkinson's disease, psychosisor diseases concerning circannual rhythm thereof. Selective agonists andantagonists against serotonin receptors other than 5-HT_(5A), 5-HT_(5B),5-HT₆ and 5-HT₇ receptors have already been launched as therapeuticagents for various kinds of diseases.

Furthermore, indole derivatives having an affinity against serotoninreceptors have been disclosed; for example, compounds of a 4-memberedring type are disclosed in WO 96/32944, WO 95/28403, EP 0738513 and soon and compounds of a 3-membered ring type are disclosed in GB 2341549,WO 98/00400, JP 99-189585A and so on. However, these indole derivativesdo not contain oxygen as an ring element. Moreover, naturally occurringheterocyclyl type of indole derivatives are described in WO 00/59909.

Under the situations mentioned above, development of novel compoundshaving an affinity against serotonin receptors and medicines containingthem have been desired.

DISCLOSURE OF INVENTION

The present inventors have intensively studied to find that tricyclicindole compounds have an affinity against serotonin receptors, andaccomplished the present invention shown below.

-   (1) A compound, prodrug, pharmaceutically acceptable salt or solvate    thereof of the formula:    wherein    -   R¹ is hydrogen;    -   R² is hydrogen or lower alkyl;    -   R³ is hydrogen, —COOR¹² (R¹² is hydrogen or ester residue) or        —CN;    -   R⁴ is hydrogen, lower alkyl, —COOR¹³ (R¹³ is hydrogen or ester        residue), —CONR¹⁴R¹⁵ (R¹⁴ and R¹⁵ are each independently        hydrogen, lower alkyl, cycloalkyl, lower alkenyl, optionally        substituted aralkyl, optionally substituted aryl, or optionally        substituted heteroaryl, or R¹⁴ and R¹⁵ taken together with a        neighboring nitrogen atom may form 5- to 7-membered        heterocycle), —CN, —NO₂, —NR¹⁶R¹⁷ (R¹⁶ and R¹⁷ are each        independently hydrogen, —CN, optionally substituted lower alkyl,        cycloalkyl, cycloalkyl(lower)alkyl, lower alkenyl, optionally        substituted aralkyl, optionally substituted aryl, optionally        substituted heteroaryl, or optionally substituted amino, or R¹⁶        and R¹⁷ taken together with a neighboring nitrogen atom may form        optionally substituted 5- to 7-membered heterocycle), —NR¹⁸COR¹⁹        (R¹⁸ and R¹⁹ are each independently hydrogen, optionally        substituted lower alkyl, cycloalkyl, cycloalkyl lower alkyl,        lower alkenyl, optionally substituted aralkyl, optionally        substituted aryl, or optionally substituted heteroaryl),        —NR²⁰COOR²¹ (R²⁰ is hydrogen, lower alkyl, cycloalkyl,        cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted        aralkyl, optionally substituted aryl, or optionally substituted        heteroaryl; R²¹ is ester residue), —NR²²SO₂R²³ (R²² is hydrogen,        lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, lower alkenyl,        optionally substituted aralkyl, optionally substituted aryl, or        optionally substituted heteroaryl; R²³ is lower alkyl,        cycloalkyl, lower alkenyl, optionally substituted aralkyl,        optionally substituted aryl, optionally substituted heteroaryl,        or lower alkylamino), —OH, lower alkoxy, —SH, or lower        alkylthio, or R³ and R⁴ taken together may form ═O, ═S, or lower        alkylenedioxy;    -   R⁵ is hydrogen, or R³ and R⁵ taken together may form a bond;    -   R⁶ is hydrogen, —COOR²⁴ (R²⁴ is hydrogen or ester residue), —CN,        or —CH₂NR²⁵R²⁶ (R²⁵ and R²⁶ are each independently hydrogen,        lower alkyl, cycloalkyl, or lower alkenyl);    -   R⁷ is hydrogen, halogen, —CN, optionally substituted lower        alkyl, cycloalkyl, cycloalkyl(lower)alkyl, optionally        substituted lower alkenyl, optionally substituted aralkyl,        optionally substituted aryl, optionally substituted heteroaryl,        optionally substituted amino, —COOR³⁴ (R³⁴ is hydrogen or ester        residue), —COR³⁵ (R³⁵ is hydrogen, lower alkyl, cycloalkyl,        lower alkenyl, optionally substituted aralkyl, optionally        substituted amino, optionally substituted aryl, or optionally        substituted heteroaryl) or —CHNOH;    -   R⁸ is hydrogen, optionally substituted lower alkyl, cycloalkyl,        cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted        aralkyl, optionally substituted aryl, optionally substituted        heteroaryl, —COR²⁷ (R²⁷ is hydrogen, lower alkyl, cycloalkyl,        lower alkenyl, optionally substituted aralkyl, optionally        substituted aryl, or optionally substituted heteroaryl, —COOR²⁸        (R²⁸ is ester residue), —SO₂R²⁹ (R²⁹ is lower alkyl, cycloalkyl,        optionally substituted lower alkenyl, optionally substituted        aralkyl, optionally substituted aryl, optionally substituted        heteroaryl) or tri-lower alkylsilyl;    -   R⁹, R¹⁰ and R¹¹ are each independently hydrogen, halogen,        optionally substituted lower alkyl, cycloalkyl,        cycloalkyl(lower)alkyl, optionally substituted lower alkenyl,        lower alkoxy, —OH, —CN, —SR³⁰ (R³⁰ is hydrogen or lower alkyl),        —CONH₂, —CHO, —CHNOH, —COOR³¹ (R³¹ is hydrogen or ester        residue), —NR³²R³³ (R³² and R³³ are each independently hydrogen        or lower alkyl), optionally substituted aryl, or optionally        substituted heteroaryl.-   (2) A compound, prodrug, pharmaceutically acceptable salt, or    solvate thereof according to the above 1, wherein R² is hydrogen.-   (3) A compound, prodrug, pharmaceutically acceptable salt, or    solvate thereof according to the above 1, wherein R³ is hydrogen.-   (4) A compound, prodrug, pharmaceutically acceptable salt, or    solvate thereof according to the above 1, wherein R⁵ is hydrogen.-   (5) A compound, prodrug, pharmaceutically acceptable salt or solvate    thereof, according to the above 1, wherein R³ and R⁵ taken together    may form a bond.-   (6) A compound, prodrug, pharmaceutically acceptable salt or solvate    thereof, according to the above 1, wherein R³ and R⁴ taken together    may form ═O, ═S or lower alkylenedioxy.-   (7) A compound, prodrug, pharmaceutically acceptable salt or solvate    thereof, according to the above 1, wherein R⁴ represents —COOR¹³    (R¹³ is hydrogen or lower alkyl), —NR¹⁶R¹⁷ (R¹⁶ and R¹⁷ are each    independently hydrogen, optionally substituted lower alkyl,    cycloalkyl, lower alkenyl, optionally substituted aralkyl,    optionally substituted amino, or R¹⁶ and R¹⁷ taken together may form    an optionally substituted 5 to 7 membered heterocyclyl ring with the    neighboring nitrogen atom), —NR¹⁸COR¹⁹ (R¹⁸ and R¹⁹ are each    independently hydrogen, optionally substituted lower alkyl or    optionally substituted aralkyl), —NR²⁰COOR²¹ (R²⁰ is hydrogen, or    lower alkyl; R²¹ is an ester moiety), —NR²²SO₂R²³ (R²² is hydrogen;    R²³ is lower alkyl or lower alkylamino), —OH, or lower alkoxy.-   (8) A compound, prodrug, pharmaceutically acceptable salt or solvate    thereof, according to the above 1, wherein R⁴ is —COOR¹³ (R¹³ is    hydrogen or methyl), —NR¹⁶R¹⁷ (R¹⁶ is hydrogen or lower alkyl, R¹⁷    is hydrogen, optionally substituted lower alkyl, cycloalkyl, lower    alkenyl, optionally substituted aralkyl, optionally substituted    amino, optionally substituted amino or R¹⁶ and R¹⁷ are taken    together may form an optionally substituted 5 to 7 membered    heterocyclyl ring with the neighboring nitrogen atom), —NR¹⁸COR¹⁹    (R¹⁸ is hydrogen, R¹⁹ is hydrogen, optionally substituted lower    alkyl or optionally substituted aralkyl), —NR²⁰COOR²¹ (R²⁰ is    hydrogen or methyl; R²¹ is methyl), —NR²²SO₂R²³ (R²² is hydrogen;    R²³ is methyl or methylamino), —OH, or lower alkoxy.-   (9) A compound, prodrug, pharmaceutically acceptable salt or solvate    thereof, according to the above 1, wherein R⁴ is —NH₂, —NHCH₃ or    —N(CH₃)₂.-   (10) A compound, prodrug, pharmaceutically acceptable salt or    solvate thereof, according to the above 1, wherein R⁶ is hydrogen,    COOCH₃, COOCH₂CH₃, CN, or CH₂NH₂.-   (11) A compound, prodrug, pharmaceutically acceptable salt or    solvate thereof, according to the above 1, wherein R⁶ is hydrogen.-   (12) A compound, prodrug, pharmaceutically acceptable salt or    solvate thereof, according to the above 1, wherein R⁷ is hydrogen,    lower alkyl, halogen, phenyl, —COOR³⁴ (R³⁴ is mentioned before),    —CHO or —CHNOH.-   (13) A compound, prodrug, pharmaceutically acceptable salt or    solvate thereof, according to the above 1, wherein R⁷ is hydrogen,    methyl, ethyl, halogen or phenyl.-   (14) A compound, prodrug, pharmaceutically acceptable salt or    solvate thereof, according to the above 1, wherein R⁸ is hydrogen,    optionally substituted lower alkyl, —COR²⁷ (R²⁷ is hydrogen, lower    alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl,    optionally substituted aryl, or optionally substituted heteroaryl),    —COOR²⁸ (R²⁸ is ester moiety), or —SO₂R²⁹ (R²⁹ is lower alkyl,    cycloalkyl, optionally substituted lower alkenyl, optionally    substituted aralkyl, optionally substituted aryl, optionally    substituted heteroaryl), or tri-lower alkylsilyl.-   (15) A compound, prodrug, pharmaceutically acceptable salt or    solvate thereof, according to the above 1, wherein R⁸ is hydrogen or    —SO₂R²⁹ (R²⁰ is mentioned before)-   (16) A compound, prodrug, pharmaceutically acceptable salt or    solvate thereof, according to the above 1, wherein all of R⁹, R¹⁰    and R¹¹ are hydrogen.-   (17) A compound, prodrug, pharmaceutically acceptable salt or    solvate thereof, according to the above 1, wherein R² is hydrogen;    R³ and R⁵ are both hydrogen or taken together may form a bond.-   (18) A compound, prodrug, pharmaceutically acceptable salt or    solvate thereof, according to the above 16 and 17, wherein R⁶ is    hydrogen, COOCH₃, COOCH₂CH₃, CN, or CH₂NH₂; R⁷ is hydrogen, lower    alkyl, halogen or phenyl; R⁸ is hydrogen, lower alkyl, COPh, or    SO₂Ph (Ph represents phenyl).-   (19) A compound, prodrug, pharmaceutically acceptable salt or    solvate thereof, according to the above 1, wherein R⁹ is hydrogen or    halogen.-   (20) A compound, prodrug, pharmaceutically acceptable salt or    solvate thereof, according to the above 1, wherein R⁹ is hydrogen.-   (21) A compound, prodrug, pharmaceutically acceptable salt or    solvate thereof, according to the above 1, wherein R¹⁰ is hydrogen.-   (22) A compound, prodrug, pharmaceutically acceptable salt or    solvate thereof, according to the above 1, wherein R¹¹ is hydrogen,    halogen, lower alkyl, optionally substituted lower alkenyl, —CN,    —SR³⁰ (R³⁰ is hydrogen or lower alkyl), —CONH₂, —CHO, —CHNOH,    —NR³²R³³ (R³² and R³³ are each independently hydrogen or lower    alkyl) or aryl.-   (23) A compound, prodrug, pharmaceutically acceptable salt or    solvate thereof, according to the above 1, wherein R¹¹ is hydrogen,    halogen, methyl, —CN, or —CONH₂.-   (24) A compound, prodrug, pharmaceutically acceptable salt or    solvate thereof, according to the above 1, wherein R¹, R², R³, R⁵,    R⁶, R⁹, and R¹⁰ is hydrogen; R⁴ is —NH₂, —NHCH₃, or —N(CH₃)₂; R⁷ is    hydrogen, halogen, lower alkyl, or phenyl; R⁸ is hydrogen or —SO₂R²⁹    (R²⁹ is mentioned before); R¹¹ is hydrogen, halogen, lower alkyl,    —CN, or —CONH₂.-   (25) A pharmaceutical composition containing a compound, prodrug,    pharmaceutically acceptable salt or solvate thereof according to any    one of the above 1-24.-   (26) A therapeutic or prophylactic medicament against the serotonin    receptors mediated diseases, comprising a compound, prodrug,    pharmaceutically acceptable salt or solvate thereof according to any    one of the above 1-24.-   (27) A therapeutic or prophylactic medicament according to the above    26, wherein the serotonine receptor is a 5-HT₆ receptor.-   (28) A therapeutic or prophylactic medicament according to the above    26, wherein the disease is that of central nervous system.-   (29) A therapeutic or prophylactic medicament according to the above    28, wherein the disease of the central nervous system is    schizophrenia, Alzheimer's disease, Parkinson's disease, depression,    anxiety, pain or migraine.-   (30) A method for treating or preventing the serotonin receptors    mediated diseases, which comprises administrating to said mammal an    effective amount of a compound, prodrug, pharmaceutically acceptable    salt or solvate thereof according to any one of the above 1-24.-   (31) Use of a compound, prodrug, pharmaceutically acceptable salt or    solvate thereof according to any one of the above 1-24, in order to    prepare a therapeutic or prophylactic medicament for the serotonin    receptors mediated diseases.

BEST MODE FOR CARRYING OUT THE INVENTION

Each group of compound (I) is explained below. Each term used herein isdefined to have meanings described below in either case of a single or ajoint use with other terms, unless otherwise noted.

“Halogen” refers to F, Cl, Br, I.

“Lower alkyl” includes a straight-chain and branched-chain C₁-C₆ alkylgroup and refers to methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, tert-butyl, n-pentyl, i-pentyl, neo-pentyl, tert-pentyl,n-hexyl and the like, preferably a C₁-C₄ alkyl group and more preferablya C₁-C₃ alkyl group, such as methyl, ethyl, n-propyl, and i-propyl.

“Lower alkenyl” includes a straight-chain and branched-chain C₂-C₆alkenyl group and refers to vinyl, allyl, 1-propenyl, 2-butenyl,3-butenyl, 1-pentenyl, prenyl, 2-hexenyl and the like, preferably vinyl,allyl or prenyl and the like.

“Lower alkoxy” includes oxy groups binding to an above mentioned loweralkyl group, and refers to methoxyl, ethoxyl, n-propoxyl, i-propoxyl,tert-butoxy, pentyloxy, hexyloxy and the like, preferably a C₁-C₄alkoxyl group and more preferably a C₁-C₃ alkoxyl group such asmethoxyl, ethoxyl, n-propoxyl, and i-propoxyl.

“Cycloalkyl” includes C₃-C₈ cycloalkyl and refers to cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and thelike, preferably a C₅-C₇ cycloalkyl group such as cyclopentyl,cyclohexyl, and cycloheptyl.

“Cycloalkyl(lower)alkyl” means an above mentioned lower alkyl groupbound with an above mentioned cycloalkyl group and refers tocyclopropylmethyl, 2-cyclopropyl ethyl and the like.

“Lower alkylthio” includes a thio group bound with an above mentionedlower alkyl group and refers to methylthio, ethylthio, i-propylthio,tert-butylthio, pentylthio, hexylthio and the like, preferablymethylthio.

“Aryl” used herein means a single or fused aromatic hydrocarbon ringsystem and refers to phenyl, naphthyl (such as α-naphthyl, andβ-naphthyl), anthryl, indenyl, phenanthryl and the like, preferablyphenyl or naphthyl.

“Lower alkylenedioxy” includes a straight-chain and branched-chain C₁-C₆alkylendioxy group, preferably methylenedioxy, ethylenedioxy, ortrimethylenedioxy, more preferably ethylenedioxy.

“Aralkyl” used herein means a lower alkyl group bound with an abovementioned aryl group, refers to benzyl, phenethyl, phenylpropyl (such as3-phenylpropyl), naphthylmethyl (such as α-naphthylmethyl),anthrylmethyl such as 9-anthrylmethyl and the like.

“Heteroaryl” used herein means a single or polycyclic aromatic ringsystem in which the ring contains the same or different heteroatomselected from the group of O, S and N.

The single aromatric ring system includes a 5- to 7-membered ring moietyin which the heterocycle contains 1 to 4 heteroatoms and refers tofuryl, thienyl, tetrazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl,thiazolyl, thiadiazolyl, pyridinyl, oxazinyl, triazinyl and the like,preferably 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl,3-pyrrolyl, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl.

Polycyclic aromatic ring system includes a di- or tri-heterocyclicmoiety in which the heterocycle contains 1 to 5 heteroatoms and refersto benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl,indazolyl, benzimidazolyl, benzoxazoly, benzothiazolyl, benzotriazolyland the like.

5- to 7-Membered heterocycle formed by “R¹⁴ and R¹⁵” or “R¹⁶ and R¹⁷”taken together with the neighboring nitrogen, refers to pyrrolydine,piperidine, azepine, piperazine, morpholine and the like, preferablypyrrolydine, piperazine or morpholine.

Substituents on the aryl, heteroaryl or heterocyclyl ring refer tohalogen, hydroxy, amino, carboxy, cyano, nitro, carbamoyl, sulfamoyl,lower alkyl (such as methyl or ethyl), halo-lower alkyl (such as —CCF₃),lower alkyl-carbamoyl (such as methylcarbamoyl), lower alkyl-sulfamoyl(such as methylsulfamoyl), lower alkoxy (such as methoxyl), loweralkoxycarbonyl (such as ethoxylcarbonyl), a 5- to 7-memberedheterocyclyl group such as isoxazolyl and the like, preferably halogen,methyl, methoxyl, trihalo-methyl such as trifluoromethyl, preferably 1to 3 of these groups can be substituted.

“Ester” residue refers to lower alkyl, optionally substituted aralkyland the like, preferably, methyl, ethyl, n-propyl, i-propyl, tert-butyl,benzyl and the like.

“Lower alkyl” or “lower alkenyl” can be optionally substituted, in whicha substituent refers to hydroxy, halogen, amino and optionally mono- ordi-lower alkyl substituted carbamoyl (such as carbamoyl, anddimethylcarbamoyl), phenyl, phenylamino, cyclohexylamino, lower alkoxy,lower alkoxycarbonyl such as methoxylcarbonyl and the like.

An optional substitutent on amino groups refers to lower alkyl, loweralkoxycarbonyl and the like.

Preferred examples are shown below.

-   (1) both of R¹ and R⁵ are hydrogen.-   (2) all of R¹, R³, and R⁵ are hydrogen.-   (3) R¹ is hydrogen; R³ and R⁴ are taken together may form a bond.-   (4) R¹ is hydrogen; R³ and R⁴ are taken together may form ═O or ═S.

Other preferred examples are shown in following tables.

TABLE 1 R² R³ R⁴ R⁶ H H H H methyl COOR¹² methyl COOR²⁴ ethyl CN ethylCN n-propyl n-propyl CH₂NR²⁵R²⁶ i-propyl i-propyl COOR¹³ CONR¹⁴R¹⁵ CNNO₂ NR¹⁶R¹⁷ NR¹⁸COR¹⁹ NR²⁰COOR²¹ NR²²SO₂R²³ OH methoxyl ethoxyln-propoxyl i-propoxyl SH methyl thio ethyl thio n-propylthioi-propylthio —O(CH₂)₂O—

TABLE 2 R⁷ R⁸ R⁹, R¹⁰, R¹¹ H H H F methyl F Cl ethyl Cl Br n-propyl Br Ii-propyl I methyl cyclopropylmethyl methyl ethyl cyclopentyl ethyln-propyl cyclohexyl n-propyl i-propyl cycloheptyl i-propylcyclopropylmethyl vinyl cyclopropylmethyl cyclopentyl allyl cyclopentylcyclohexyl prenyl cyclohexyl cycloheptyl benzyl cycloheptyl vinylphenethyl vinyl allyl phenyl allyl prenyl 2-furyl prenyl benzyl 3-furylOH phenethyl 2-pyridinyl methoxyl phenyl 3-pyridinyl ethoxyl 2-furyl4-pyridinyl n-propoxyl 3-furyl 2-pyrrolyl i-propoxyl 2-pyridinyl3-pyrrolyl CN 3-pyridinyl 2-thienyl CHO 4-pridinyl 3-thienyl SCH₃2-pyrrolyl COR²⁷ CH═N—OH 3-pyrrolyl COOR²⁸ CONH₂ 2-thienyl SO₂R²⁹ phenyl3-thienyl Si(iPr)₃ CH═CHCO₂CH₃ CN

TABLE 3 R¹², R¹³ R¹⁴, R¹⁶ R¹⁵, R¹⁷ H H H methyl methyl methyl ethylethyl ethyl n-propyl n-propyl n-propyl i-propyl i-propyl i-propylt-butyl cyclopropyl methyl cyclopropylmethyl benzyl cyclopentylcyclopentyl cyclohexyl cyclohexyl cycloheptyl cycloheptyl allyl allylprenyl prenyl benzyl benzyl phenethyl phenethyl phenyl phenyl 2-furyl2-furyl 3-furyl 3-furyl 2-pyridinyl 2-pyridinyl 3-pyridinyl 3-pyridinyl4-pyridinyl 4-pyridinyl 2-pyrrolyl 2-pyrrolyl 3-pyrrolyl 3-pyrrolyl2-thienyl 2-thienyl 3-thienyl NHBoc cyclopropyl CH₂CF₃ —CH₂CH₂CH₂CH₂——CH₂CH₂CH₂CH₂CH₂— —CH₂CH₂CH₂CH₂CH₂CH₂— —CH═CH—CH═CH— —CH₂CH₂NHCH₂CH₂——CH₂CH₂NCH₃CH₂CH₂— —CH₂CH₂OCH₂CH₂—

TABLE 4 R²¹ R¹⁸, R¹⁹, R²⁰, R²² R²³ methyl H methyl ethyl methyl ethyln-propyl ethyl n-propyl i-propyl n-propyl i-propyl t-butyl i-propylcyclopropylmethyl benzyl cyclopropylmethyl cyclopentyl cyclopentylcyclohexyl cyclohexyl cycloheptyl cycloheptyl vinyl allyl allyl prenylprenyl benzyl benzyl phenethyl phenethyl phenyl phenyl 2-furyl 2-furyl3-furyl 3-furyl 2-pyridinyl 2-pyridinyl 3-pyridinyl 3-pyridinyl4-pyridinyl 4-pyridinyl 2-pyrrolyl 2-pyrrolyl 3-pyrrolyl 3-pyrrolyl2-thienyl 2-thienyl 3-thienyl 3-thienyl CH₂N(CH₃)₂ NHCH₃ CF₃CH₂NH-cyclohexyl

TABLE 5 R²⁴ R²⁵, R²⁶ H H methyl methyl ethyl ethyl n-propyl n-propyli-propyl i-propyl t-butyl cyclopropylethyl benzyl cyclopentyl cyclohexylcycloheptyl vinyl allyl prenyl

TABLE 6 R²⁷ R²⁸ R²⁹ H methyl methyl methyl ethyl ethyl ethyl n-propyln-propyl n-propyl i-propyl i-propyl i-propyl t-butyl cyclopropylmethylcyclopropylmethyl benzyl cyclopentyl cyclopentyl cyclohexyl cyclohexylcycloheptyl cycloheptyl vinyl vinyl allyl allyl prenyl prenyl benzylbenzyl phenethyl phenethyl phenyl phenyl 2-furyl 2-furyl 3-furyl 3-furyl2-pyridinyl 2-pyridinyl 3-pyridinyl 3-pyridinyl 4-pyridinyl 4-pyridinyl2-pyrrolyl 2-pyrrolyl 3-pyrrolyl 3-pyrrolyl 2-thienyl 2-thienyl3-thienyl 3-thienyl α-naphthyl mono or diCl-phenyl CF₃-phenyl Br-phenylmono or dimethoxy phenyl Br-di F-phenyl phenyl vinyl mono or diF-phenylCl-thienyl isoxyazolylthienyl

The following cases are more preferable.

R² is more preferably hydrogen or methyl and particularly preferable ishydrogen.

R³ and R⁵ are more preferably both hydrogen or taken together may form abond and particularly preferable is hydrogen.

R⁴ is preferably —COOR¹³ (R¹³ is hydrogen or lower alkyl), —NR¹⁶R¹⁷ (R¹⁶and R¹⁷ is each independently hydrogen, optionally substituted loweralkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl,optionally substituted amino, or R¹⁶ and R¹⁷ taken together may formoptionally substituted 5- to 7-membered heterocyclyl with theneighboring nitrogen atom), —NR¹⁸COR¹⁹ (R¹⁸ and R¹⁹ are eachindependently hydrogen, optionally substituted lower alkyl or optionallysubstituted aralkyl), —NR²⁰COOR²¹ (R²⁰ is hydrogen, or lower alkyl; R²¹is ester residue), —NR²²SO₂R²³ (R²² is hydrogen; R²³ is lower alkyl orlower alkylamino), —OH, lower alkoxy. R⁴ is preferably —COOR¹³ (R¹³ ishydrogen or methyl), —NR¹⁶R¹⁷ (R¹⁶ is hydrogen or lower alkyl, R¹⁷ ishydrogen, optionally substituted lower alkyl, cycloalkyl, lower alkenyl,optionally substituted aralkyl, optionally substituted amino, or R¹⁶ andR¹⁷ taken together may form optionally substituted 5- to 7-memberedheterocyclyl with the neighboring nitrogen atom), —NR¹⁸COR¹⁹ (R¹⁸ ishydrogen, R¹⁹ is hydrogen, optionally substituted lower alkyl oroptionally substituted aralkyl), —NR²⁰COOR²¹ (R²⁰ is hydrogen or methyl;R²¹ is methyl), —NR²²SO₂R²³ (R²² is hydrogen; R²³ is methyl ormethylamino), —OH, lower alkoxy. R⁴ is preferably —NH₂, —NHCH₃, or—N(CH₃)₂.

R⁶ is more preferably hydrogen, COOMe (Me is methyl), COOEt (Et isethyl), CN, or CH₂NH₂, more preferably hydrogen.

R⁷ is preferably hydrogen, lower alkyl, halogen, phenyl, —COOR³⁴ (R³⁴ ishydrogen or ester residue), —CHO or —CHNOH, more preferably hydrogen,methyl, ethyl, halogen, or phenyl.

R⁸ is more preferably hydrogen, optionally substituted lower alkyl,—COR²⁷ (R²⁷ is hydrogen, lower alkyl, cycloalkyl, lower alkenyl,optionally substituted aralkyl, optionally substituted aryl, oroptionally substituted heteroaryl), —COOR²⁸ (R²⁸ is ester residue), or—SO₂R²⁹ (R²⁹ is lower alkyl, cycloalkyl, optionally substituted loweralkenyl, optionally substituted aralkyl, optionally substituted aryl,optionally substituted heteroaryl), or tri-lower alkyl silyl, morepreferably hydrogen or —SO₂R²⁹ (R²⁹ is lower alkyl, cycloalkyl,optionally substituted lower alkenyl, optionally substituted aralkyl,optionally substituted aryl, optionally substituted heteroaryl). R²⁹ ismore preferably mono- or di-Cl-phenyl, CF₃-phenyl, Br-phenyl, mono- ordi-methoxyphenyl, phenylvinyl, mono- or di-F-phenyl, Cl-thienyl,naphthyl.

R⁹ is preferably hydrogen or halogen, more preferably hydrogen.

R¹⁰ is preferably hydrogen.

R¹¹ is preferably hydrogen, halogen, lower alkyl, optionally substitutedlower alkenyl, —CN, —SR³⁰ (R³⁰ is hydrogen or lower alkyl), —CONH₂,—CHO, —CHNOH, —NR³²R³³ (R³² and R³³ is each independently hydrogen orlower alkyl) or aryl, more preferably hydrogen, halogen, methyl, —CN, or—CONH₂.

In a preferred compound among compound (I), R¹, R², R³, R⁵, R⁶, R⁹, andR¹⁰ are hydrogen; R⁴ is —NH₂, —NHCH₃, or —N(CH₃)₂; R⁷ is hydrogen,halogen, lower alkyl or phenyl; R⁸ is hydrogen or —SO₂R²⁹ (R²⁹ ismentioned before); R¹¹ is hydrogen, halogen, lower alkyl, —CN, or—CONH₂.

A produg of compound (I) is a derivative of compound (I), which has achemically or metabolically decomposible group and can get back to apharmaceutically active present invention compound by the solvolysis orunder physiological conditions in vivo. Methods of selection andproduction of a suitable prodrug derivative has been disclosed, forexample in Design of Prodrugs, Elsevier, Amsterdam 1985. Having acarboxylic acid group, the original acidic compound can be exemplifiedto be reacted with an appropriate alcohol derivative to give the esterderivative or reacted with a suitable amino derivative to give the amidederivative as the prodrug. Having a hydroxyl group, the hydroxylcompound for example can be exemplified to be reacted with appropriateacid halides or acid anhydrides to give the acyloxy derivative as theprodrug. Having an amino group, the amino compound can be exemplified tobe reacted with a suitable acid halide or acid anhydride to give theamide compound as the prodrug.

A pharmaceutically acceptable salt of compound (I) or the prodrug refersto those salts, which are obtained by reacting with inorganic acids,inorganic bases, ammonia, organic bases, inorganic acids, organic acids,basic amino acids, ionic halogen and the like, or the internal salt. Theinorganic base refers to alkaline metals (Na, K and the like),alkaline-earth metal (Ca, Mg and the like). Organic base refers totrimethylamine, triethylamine, corrine, procaine, ethanolamine and thelike. The inorganic acid refers to hydrochloric acid, hydrogen bromide,sulfuric acid, nitric acid, phosphoric acid, and the like. The organicacid refers to p-toluenesulfonic acid, methanesulfonic acid, formicacid, trifluoroacetic acid, maleic acid and the like. Basic amino acidrefers to lysine, arginine, ornithine, histidine and the like.

A solvate of compound (I) refers to the hydrate or alcholate and thelike. The racemic or the optically active compound (I) and the like areall included in the present invention.

Compound (I) can be prepared from indole derivatives and the like asstarting material which are well known or can be obtained easily by thesynthesis. General method of preparation is shown below.

(The 1st Process)

Compound (III) can be obtained by reacting indole derivative (II) withvinyl compound (IV) (X¹ is H) in the presence of a base. This reactioncan be accomplished fundamentally according to the Baylis-Hillman vinylalkylation condition. The reaction temperature can be exemplified to be−20-50° C. and the solvent can be illustrated to be tetrahydrofuran(THF), dioxane, dichloromethane, chloroform and the like. Excess vinylcompound can be used as the solvent, also. As the base, 1,4-diazabicyclo[2,2,2]octane (DABCO), tri-n-butylphosphine and the like can beexemplified. The reaction time is ordinarily several hours to severaldays.

The preparation of compound (III) is also possible by reacting theacetylene compound R²C≡CR⁴ (V) with the vinyl compound (III) (X¹ isAl(i-Bu)₂), obtained from compound R²C≡CR⁴ (V) anddiisopropylaluminumhydride (DIBAL). The reaction to the vinyl aluminumcompound can be carried out according to a similar manner of well-knownmethods (for example: the method is disclosed in J. Org. Chem., 1988,53, 1037.). The reaction temperature is exemplified to be ordinarily−100 to 50° C. and the solvent is tetrahydrofuran (THF), dioxane,dichloromethane and the like. The reaction temperature is normallyseveral hours to tens of hours.

(The 2nd Process)

Compound (III) is cyclized under a Mitsunobu reaction condition to givecompound (I-1) of the present invention. The Mitsunobu reaction can becarried out according to the well-known ordinary method (for example, amethod disclosed in Synthesis, 1981,1.). The reaction temperature usedare exemplified to be −50-50° C. and the solvent used are exemplified tobe tetrahydrofuran (THF), dioxane, benzene, toluene, dichloromethane andthe like, respectively. Among reagents, 1,1′-(azodicarbonyl)-diethylester, 1,1′-(azodicarbonyl)-diisopropyl ester,1,1′-(azodicarbonyl)-dipieridine and the like are used in this reactionas diazocarboxylic acid ester derivatives. Further, triphenylphosphine,tri-n-butylphosphine and the like can be exemplified as phosphinederivatives. The reaction time is ordinarily several hours to tens ofhours.

Furthermore, compound (I-1) can be obtained by cyclizing compound (III)in the presence of base. Moreover, in order to increase the yield of thereaction, it is preferable that the secondary hydrokyl group is firstchanged to the appropriate removable group such as acetoxyl group andthe like and then the cyclization reaction is carried out in thepresence of base. The reaction temperature can be exemplified to be0-100° C. and the solvents can be exemplified to be tetrahydrofuran(THF), dioxane, toluene, acetone, acetonitrile, and the like,respectively. Potassium carbonate, NaH, pyridine, triethylamine and thelike can be exemplified as the base used. The reaction time isordinarily several hours to tens of hours.

Furthermore, it is possible in the 1st process to convert to compound(I-1) through the only one step by reacting compound (II) with compound(IV) (X¹ is H) at relatively high temperature (20-50° C.).

Furthermore, it is possible to convert to compound (I-1) through theonly one step by reacting compound (II) and compound (IV) (X¹ is—PO(OMe)₂) under the presence of base. The reaction temperature isordinarily −20-50° C. Tetrahydrofuran (THF), dioxane, toluene,dichloromethane and the like can be exemplified as the solvent.Potassium tert-butoxyde and the like can be exemplified as the base. Thereaction time is ordinarily several hour to tens of hours.

According to the above reaction, preferably a compound, in which R⁴ incompound (I-1) is electron-withdrawing group, is obtained. As theelectron-withdrawing group, ester group, carboxylic acid group, cyanogroup, amide group, aldehyde group, nitro group and the like areexemplified.

Compound (I-1) is a compound (I) in the present invention, where R¹ andR⁶ are both hydrogen and R³ and R⁵ taken together may form a bond.Compound (I-1) can be derived to other compounds of the presentinvention by chemical modifications. For example, compound (I-1), whereR⁴ is carboxylic acid, can be transferred to the various kinds of esterand amide compounds by converting to the acid chloride with thionylchloride and the like or to the acid anhydride with ethyl chloroacetateand the like under the existence of base such as triethylamine, followedby reacting with the various kinds of alcohol or amino derivatives.Furthermore, compound (I-1) can also be transferred to the various kindsof ester and amide compounds by using appropriate condensing agents suchas dicyclohexylxarbodiimide, carbonyldiimidazole and the like. Further,if the reaction is carried out according to Curtius reaction or Hofmannreaction, compound in which R⁴ is carbamate can be obtained. Moreover,compound in which R⁴ is hydroxy (or R³ and R⁴ taken together may form═O) can be prepared by the hydrolysis of the compound in which R⁴ iscarbamate. Furthermore, by reduction catalytically or with sodiumborotriacetoxyhydride under the presence of appropriate base, compound,in which R³ and R⁴ taken together may form ═O, can be transferred tocompounds in which R⁴ is various kind of N-alkyl groups.

(The 3rd Process))

Compound (I-2) of the present invention can be obtained by the reductionof compound (I-1). Compound (I-2) is a compound (I) of the presentinvention, where all of R¹, R³, R⁵ and R⁶ are hydrogen. The reductionreaction is carried out preferably by a catalytic reduction (Pd/C, H₂)thereof. By further chemical modifications of compound (I-2), anothercompound of the present invention can be obtained. For example, in thecase where R⁴ is primary or secondary amino group, compound (I-2) can beconverted to the various kinds of N-sulfonyl or N-acyl compounds byreacting with various kinds of sulfonyl chloride or acyl chloride in thepresence of base such as triethylamine and the like. Furthermore,compound (I-2) can be transferred to various kinds of N-alkyl compoundsby reacting with various kinds of alkyl halide under the presence ofbase such as triethylamine and the like or by reduction catalytically orwith sodium triacetoxyborohydride in the presence of various kinds ofaldehydes or ketones.

Compound (I-3) of the present invention can be obtained by cyclizationof indole derivative (IV) (X² is a removing group such as lower alkoxyand the like) preferably under the presence of base. Compound (I-3) is acompound in which R³ and R⁵ taken together may form a bond and R⁴ is ahydroxy group in compound (I). As the solvent, ether, tetrahydrofuran(THF), dioxane and the like are exemplified. NaH, sodium metal,potassium tert-butoxyde lithium bis(trimethylsilyl)amide and the likeare exemplified as the base. The reaction time is ordinarily severalhours to tens hours. By this reaction, a preferred compound is obtained,in which R⁶ is an electron-withdrawing group such as carboxylic acidgroup, ester group, cyano group.

Moreover, R¹ and R² are preferably hydrogen in the above preparations.Furthermore, if necessary, the group can be protected before thereaction and de-protected after the reaction by the well-known method.For example, R⁸ in the intermediate is preferably an amino protectinggroup such as Boc. Compounds obtained by the above method of preparationof the present invention can be transferred to another compound of thisinvention by further chemical modifications of well-known reaction suchas oxidation, reduction, protection, deprotection, rearrangementreaction, halogenation, hydroxylation, alkylation, alkylthiolation,demethylation, O-alkylation, O-acylation, N-alkylation, N-alkenylation,N-acylation, N-cyanation, N-sulfonylation, coupling reaction usingtransition metals and the like.

Having an affinity against various kinds of serotonin receptors,compound (I) has functions as the agonist or antagonist. Therefore,compound (I) is useful as a therapeutic or prophylactic medicine tovarious serotonin receptor mediated diseases, such as diseases ofcentral nervous systems such as sleep-awakening lesion, circadian rhythmlesion, anxiously mental disorder, schizophrenia, cerebral stroke,dementia, pain, Alzheimer's disease, Parkinson's disease, depression,anxiety, megrim and the like. A specifically preferable compound (I)described above has an affinity against 5HT_(1A), 5HT₆, 5HT₇ amongserotonin receptors and more preferably has a high selective affinityagainst 5HT₆. Increase of the selectivity against 5HT₆ can be achievedpreferably by introducing various kinds of substituents to R⁷ and R¹¹and so on. Then, compound (I) is useful to the selectively 5HT₆ receptormediated diseases among the diseases of central nervous system (forexample, schizophrenia, Alzheimer's disease, Parkinson's disease,depression, anxiety, migraine and the like).

Compound (I) can be administrated orally or parenterally to mammalsincluding human. Granule, tabula, capsules, injections, suppositoriumand the like can be exemplified as an admirable dosage form. Inpharmaceutical manufacturing, if necessary, following various additiveagents can be used, for example remedium constituens (lactose, mannitol,crystalline cellulose, starch and the like), disintegrators (carmellose,hydroxypropylmethyl cellulose, polyvinylpolypyrrolidone and the like),binding agent (methylcellose, hydroxypropylcellose, cellose,poloyvinylalcohol and the like), lubricant (Magnesium stearate, talc andthe like), stabilizing agent, coloring agent, coating material. Dosagevaries depending on the examinee's age, body weight, condition ofdiseases and dosage forms and so on. Generally, dosage is ca. 0.001 mgto 1 g/day to an adult in oral or parenteral administration. Number ofadministration time is one to several times/day.

Examples of this invention are described below without limiting thepresent invention thereto. “Ex” in the Scheme of reaction corresponds tothe number of Example, e.g. “Ex 1” means compound (1) obtained by theprocedure cited in Example 1.

(Abbreviated Words)

-   Me=methyl; Et=ethyl; tBu=t-butyl; nPr=n-propyl; Ph=phenyl;    Ts=p-toluene sulfonyl; Bn=benzyl; Ms=methanesulfonyl

EXAMPLE 1 OF REFERENCE

4-Hydroxyindole-3-carbaldehyde (1-1) (R⁷═R¹¹═H)

Phosphorous oxychloride 7.35 ml was added dropwise to drydimethylformamide 15 ml under cooling in ice-methanol bath and themixture was stirred for 15 min. Then, a solution of the 4-hydroxyindole5.0 g in dry dimethylformamide 10 ml was added dropwise to the mixtureunder cooling in ice and the mixture was stirred for 2 h at roomtemperature. Water was added under cooling in ice to the mixture, whichwas made alkaline with a 30% aqueous sodium hydroxide solution and wasstirred for 15 min. Then, the mixture was acidified to pH 4 with 5N-HCland the precipitate was collected by filtration, washed with water anddried to give the titled compound 4.99 g as crude crystalline materials.Yield 82%. Crude crystalline materials are recrystallized from methanolto give yellow crystals m.p. 190-193° C.

¹H-NMR(DMSO-d₆): 6.54 (1H, dd, J=8.1, 0.9 Hz), 6.95 (1H, dd, J=8.1, 0.9Hz), 7.13 (1H, t, J=8.1 Hz), 8.37 (1H, s), 9.64 (1H, s), 10.54 (1H, brs), 12.35 (1H, br s).

Following compounds were obtained, according to the similar treatment.

Compd m.p. No R⁷ R¹¹ (° C.) ¹H-NMR (DMSO-d₆) 1-2 Ph H 239-247 6.57 (1H,dd, J=8.1, 0.9 Hz), 6.95 (dec.) (1H, dd, J=8.1, 0.9 Hz), 7.17 (1H, t,J=8.1 Hz), 7.61-7.82 (5H, m), 9.56 (1H, s), 11.05 (1H, s), 12.67 (1H, brs) 1-3 Me Me 269-272 2.16 (3H, s), 2.66 (3H, s), 6.72 (1H, d, (dec.)J=8.1 Hz), 6.93 (1H, d, J=8.1 Hz), 9.64 (1H, br s), 11.05 (1H, s), 12.14(1H, br s)

EXAMPLE 2 OF REFERENCE

3-Formyl-4-hydroxyindole-1-carboxylic acid tert-butyl ester (2-1)(R⁷═R¹¹═H)

A mixture of the 3-formyl-4-hydroxyindole (1-1) 323 mg,di-tert-butyldicarbonate 458 mg, dimethylaminopyridine 12.5 mg andacetonitrile 25 ml was stirred under cooling in ice for 3 h. The solventwas removed under reduced pressure and the residue obtained wasrecrystallized from acetone-isopropyl ether to give the titled compoundas pale yellow crystals, m.p. 159-161° C.(dec.), 389 mg. Yield 74%.

¹H-NMR(CDCl₃): 1.71 (9H, s), 6.84 (1H, dd, J=8.1, 0.9 Hz), 7.31 (1H, t,J=8.1 Hz), 7.61 (1H, dd, J=8.1, 0.9 Hz), 8.25 (1H, s), 9.76 (1H, d,J=0.6 Hz), 10.13 (1H, s).

Following compounds were obtained, according to the similar treatment.

Compd m.p. No R⁷ R¹¹ (° C.) ¹H-NMR (CDCl₃) 2-2 Ph H 154-155 1.26 (9H,s), 6.86 (1H, dd, J=8.4, (dec.) 0.9 Hz), 7.33 (1H, t, J=8.4 Hz),7.43-7.53 (5H, m), 7.66 (1H, dd, J=8.4, 0.9 Hz), 9.36 (1H, s), 10.64(1H, s) 2-3 Me Me 177-179 1.71 (9H, s), 2.30 (3H, s), 2.88 (3H, s),(dec.) 7.09 (1H, d, J=8.4 Hz), 7.39 (1H, d, J=8.4 Hz), 9.90 (1H, br s),10.92 (1H, s)

EXAMPLE 3 OF REFERENCE

5-Bromo-3-formyl-4-hydroxyindole-1-carboxylic acid tert-butyl ester(2-4)

Compound (2-1) 26.1 g was suspended in dry tetrahydrofuran 260 ml andchloroform 260 ml. Pyridinium bromide perbromide 33.6 g was added to thesuspension under cooling in ice and the mixture was stirred at roomtemperature for 4.5 h. An aqueous sodium hydrogen carbonate 16.77 gsolution was added to the reaction mixtures, which were extracted withchloroform. The extracts were washed with water, dried over anhydrousmagnesium sulfate, concentrated up to the deposition of crystals anddiluted with isopropanol. Appeared crystals were collected by filtrationto give the titled compound as yellow crystals. 29.1 g. Yield 86%. m.p.239-242° C.(dec.)

¹H-NMR(CDCl₃): 1.71 (9H, s), 7.52 (2H, s), 8.24 (1H, s), 9.75 (1H, s),10.91 (1H, br s).

Scheme of Reactions, Examples 1-5

Example 1 7H-6-Oxa-2-azabenzo[c,d]azulene-2,8-dicarboxylic acid2-tert-butyl ester 8-methyl ester (3-1) (R⁷═R¹¹═H)

(Method 1)

60% Sodium hydride 23.0 mg was suspended in dry tetrahydrofuran 4 ml.Compound (2-1) 123 mg and trimethyl-2-phosphonoacrylate 116 μl wereadded with cooling in ice under nitrogen atmosphere and the mixture wasstirred for 19 h. Water was added to the mixture with cooling in ice andthe mixture was extracted with ethyl acetate. The extracts were washedwith water, dried over anhydrous magnesium sulfate and chromatographedon silica gel 25 g in ethyl acetate:hexane (1:10) to give the titledcompound (3-1) as colorless crystals, 46 mg. Yield 30%.

¹H-NMR(CDCl₃): 1.69 (9H, s), 3.84 (3H, s), 5.06 (2H, s), 6.85 (1H, dd,J=7.5, 0.6 Hz), 7.24 (1H, t, J=7.5 Hz), 7.74 (1H, s), 7.77 (1H, d, J=7.5Hz), 8.00 (1H, s).

(Method 2)

Compound (2-1) 140 mg, 1,4-diazabicyclo[2.2.2]octane 70 mg was suspendedin methyl acrylate 1.4 ml and the suspension was stirred at roomtemperature for 4 days. Ethyl acetate was added to the reaction mixturesand the insoluble materials were filtered off. The filtrate wasconcentrated under reduced pressure and chromatographed on silica gel 25g in ethyl acetate:hexane (1:10) to give titled compound (3-1) ascolorless crystals 59 mg. Yield 34%.

(Method 3)

(a) 4-Hydroxy-3-(1-hydroxy-2-methoxycarbonylallyl)indole-1-carboxylicacid tert-butyl ester (4-1) (R⁷═R¹¹═H)

Compound (2-1) 140 mg and 1,4-diazabicyclo[2.2.2]octane 70 mg weresuspended in methyl acrylate 1.4 ml with cooling in ice and thesuspension was stirred at 4° C. for 24 h. The reaction mixtures waschromatographed on silica gel in ethyl acetate:hexane several times togive the titled compound (4-1) as a colorless oil 178 mg. Yield 96%.

¹H-NMR (CDCl₃): 1.66 (9H, s), 3.86 (3H, s), 5.05 (1H, br s), 5.63 (1H,s), 5.81 (1H, s), 6.39 (1H, s), 6.78 (1H, dd, J=8.1, 0.9 Hz), 7.24 (1H,t, J=8.1 Hz), 7.31 (1H, s), 7.67 (1H, d, J=8.1 Hz), 9.10 (1H, br s).

Following compounds were obtained, according to the similar treatment.

Compd m.p. No R⁷ R¹¹ (° C.) ¹H-NMR (CDCl₃) 4-2 Ph H 121-122 1.21 (9H,s), 3.82 (3H, s), 5.01 (1H, br s), 5.51 (2H, s), 6.35 (1H, s), 6.81 (1H,dd, J=7.8, 0.6 Hz), 7.28 (1H, t, J=8.4 Hz), 7.38-7.40 (5H, m), 7.83 (1H,dd, J=8.4, 0.6 Hz), 9.14 (1H, s) 4-3 Me Me 155-156.5 1.68 (9H, s), 2.29(3H, s), 2.48 (3H, s), 3.87 (3H, s), 5.14 (1H, br s), 5.37 (1H, s), 5.96(1H, s), 6.30 (1H, s), 7.05 (1H, d, J=8.4 Hz), 7.56 (1H, d, J=8.4 Hz),9.27 (1H, s) 4-4 H Br Colorless 1.66 (9H, s), 3.85 (3H, s), 5.13 (1H, d,oil J=5.4 Hz), 5.62 (1H, s), 5.82 (1H, d, J=5.4 Hz), 6.39 (1H, s), 7.32(1H, s), 7.44 (1H, d, J=8.7 Hz), 7.57 (1H, d, J=8.7 Hz), 9.59 (1H, br s)

(b) 7H-6-Oxa-2-azabenzo[c,d]azulene-2,8-dicarboxylic acid 2-tert-butylester 8-methyl ester (3-1)

Triethylamine 20.1 mg, 1,1′-(azodicarbonyl)-dipiperidine 42.0 mg andtriphenylphosphine 43.9 mg were dissolved in dry tetrahydrofuran 1 ml.Compound (4-1) 37 mg was added to the solution with cooling in ice undernitrogen. The mixture was stirred at room temperature for 17 h. Waterwas added with cooling in ice and the reaction mixture was extractedwith ethyl acetate. The extracts were washed with water, dried overanhydrous magnesium sulfate and chromatographed on silica gel 15 g inethyl acetate:hexane (1:3) to give titled compound (3-1) as colorlesscrystals, 17. mg. Yield 48%.

(c) 7H-6-Oxa-2-azabenzo[c,d]azulene-2,8-dicarboxylic acid 2-tert-butylester 8-methyl ester (3-1) (R⁷═R¹¹═H)

Acetic anhydride 0.38 ml was added to a solution of compound (4-1) 1.32g in pyridine 13.1 ml with cooling in ice under nitrogen. The mixturewas stirred at that temperature for 1 h The solvent was removed bydistillation under reduced pressure and the residue obtained waschromatographed on silica gel 60 g in ethyl acetate:hexane (1:3) to givea yellow oil 860 mg. The oily compound 747 mg was dissolved in dioxane 7ml and potassium carbonate 530.5 mg was added. The mixture was stirredat 80° C. for 6 h, filtered through cerite and chromatographed on silicagel 40 g in ethyl acetate:hexane (1:10) to give the titled compound(3-1) as colorless crystals, 501 mg. Yield 40%, m.p. 124-126° C.(recrystallized from isopropanol)

Following compounds were obtained, according to the similar treatment.

Compd m.p. No R⁷ R¹¹ (° C.) ¹H-NMR (CDCl₃) 3-2 Ph H 151-152 1.26 (9H,s), 3.75 (3H, s), 5.08 (2H, s), 6.87 (1H, dd, J=8.1, 0.9 Hz), 7.27 (1H,t, J=8.1 Hz), 7.35-7.49 (5H, m), 7.65 (1H, s), 7.87 (1H, dd, J=8.1, 0.9Hz) 3-3 Me Me 112-114 1.69 (9H, s), 2.31 (3H, s), 2.70 (3H, s), 3.84(3H, s), 5.03 (2H, s), 7.04 (1H, d, J=8.4 Hz), 7.61 (1H, d, J=8.4 Hz),8.07 (1H, s) 3-4 H Br 160-161 1.68 (9H, s), 3.84 (3H, s), 5.14 (2H, s),7.46 (1H, d, J=9.0 Hz), 7.68 (1H, d, J=9.0 Hz), 7.74 (1H, s), 7.99 (1H,s)(Method 4)

4-Hydroxy-3-(1-hydroxy-2-methoxycarbonylallyl)-2,5-dimethylindole-1-carboxylicacid tert-butyl ester (4-3) (R⁷═R¹¹═H)

Diisobutylaluminumhydride (0.9 mol/l hexane solution) 50 ml was added toa mixture of hexamethylphosphorous triamide (8.96) g and drytetrahydrofuran 80 ml with cooling in ice under a nitrogen atmosphere.The mixture was stirred for 30 min. Methyl propiorate 3.78 g was addedand he mixture was stirred for 1 h with cooling in ice. Compound (2-3)4.36 g was added to the reaction mixture, which was stirred for 10 minand then at room temperature for 2 h. 1N—HCl 50 ml was added withcooling in ice and the mixture was extracted with ethyl acetate. Theextracts were washed with 1N—HCl, water, brine and dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residueobtained was chromatographed on silica gel 130 g in ethyl acetate:hexane(1:4) to give colorless crystals which were recrystallized from ethylacetate-hexane to give the titled compound, 4.47 g. Yield 80%, m.p.155-156.5° C.

Example 2 2,7-Dihydro-6-oxa-2-azabenzo[c,d]azulene-8-carboxylic acid(5-1) (R⁷═R¹¹═H)

The above obtained compound (3-1) 1.01 g was dissolved intetrahydrofuran 15 ml and 1 N sodium hydroxide 15 ml was added to thesolution. The mixture was stirred for 1 h. Methanol 7.5 ml was added.The mixture was stirred at 50° C. for 3 h, acidified with 2N—HCl 7.5 mlto weakly acidic with cooling in ice and extracted with ether. Theextracts were washed with brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure to give a yellow solid, whichwas recrystallized from methanol to give the titled compound (5-1), m.p.230° C.(dec.) as yellow crystals, 450 mg. From the mother liquor, thesecond crop 134 mg was obtained by crystallization from isopropanol.Yield 88%.

¹H-NMR (CD₃OD): 4.98 (2H, s), 6.60 (1H, m), 7.02-7.08 (2H, m), 7.55 (1H,s), 8.19 (1H, s).

Following compounds were obtained, according to the similar treatment.

Compd m.p. No R⁷ R¹¹ (° C.) ¹H-NMR (DMSO-d₆) 5-2 Ph H 218-220 4.98 (2H,s), 6.59-6.60 (1H, m), (dec.) 7.06-7.13 (2H, m), 7.51-7.68 (5H, m), 8.05(1H, s), 12.27 (1H, br s) 5-3 Me ME 203-206 2.20 (3H, s), 2.48 (3H, s),4.87 (2H, s), (dec.) 6.84-6.89 (2H), 8.03 (1H, s), 11.69 (1H, s), 12.03(1H, br s) 5-4 H Br 210-215 4.97 (2H, s), 7.07 (1H, d, J=8.4 Hz), (dec.)7.27 (1H, d, J=8.7 Hz), 7.83 (1H, s), 8.09 (1H, s), 12.07 (1H, s)

Example 3 (2,7-Dihydro-6-oxa-2-azabenzo[c,d]azulen-8-yl)carbamic acidtert-butyl ester (6-1) (R⁷═H)

Triethylamine 0.38 ml and chloroethyl carbonate 0.26 ml were added to asolution of the compound obtained by Ex. 2 (5-1) 530 mg in drytetrahydrofuran 5 ml with cooling in ice-methanol bath and the mixturewas stirred for 30 min. Then an aqueous solution of sodium azide 320mg/water 2 ml was added dropwise and the mixture was stirred for 4 hwith cooling in ice-methanol bath. Water was added and the reactionmixture was extracted with ethyl acetate. The extracts were washed withbrine and dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give a yellow solid. The residue obtained wassuspended in toluene 20 ml and heated under reflux at 125° C. for 20 minand concentrated under reduced pressure. The residue obtained was againsuspended in t-butanol 20 ml, heated at 100° C. for 2.5 h andconcentrated under reduced pressure. The residue obtained waschromatographed on silica gel 50 g in ethyl acetate:hexane (1:3) to givebrown crystals, which was recrystallized from ether-petrolether to givethe titled compound (6-1) m.p. 125-130° C. (dec.) as pale browncrystals, 436 mg. Yield 62%.

¹H-NMR (CDCl₃): 1.50 (9H, s), 4.76 (2H, s), 6.01 (1H, br s), 6.64 (1H,dd, J=7.2, 1.2 Hz), 6.98-7.12 (3H, m), 8.17 (1H, br s).

Following compounds were obtained, according to the similar treatment.

Compd m.p. No R⁷ (° C.) ¹H-NMR (CDCl₃) 6-2 Ph 201-202 1.49 (9H, s), 4.90(2H, br s), 6.11 (1H, br s), (dec.) 6.67 (1H, m), 6.88-7.41 (5H, m),7.49 (1H, m), 7.59 (1H, d, J=8.4 Hz), 8.24 (1H, br s)

Example 4 (2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[c,d]azulen-8-yl)carbamicacid tert-butyl ester (7-1) (R⁷═H)

5% Pd/C 100 mg was added to a solution of the compound obtained in Ex. 3460 mg in methanol 10 ml. The mixture was stirred in a hydrogenatmosphere for 1.5 h. The catalyst was filtered off and the filtrate wasconcentrated under reduced pressure. The residue obtained waschromatographed on silica gel in ethyl acetate:hexane (1:3) to give thetitled compound (7-1) as a reddish oil, 390 mg. Yield 84%.

¹H-NMR (CDCl₃): 1.41 (9H, s), 2.98-3.10 (1H, m), 3.26-3.38 (1H, m), 4.23(1H, d, J=12.0 Hz), 4.27-4.40 (1H, m), 4.48-4.58 (1H, m), 6.67 (1H, dd,J=7.2, 0.9 Hz), 6.98 (1H, br s), 7.02 (1H, dd, J=7.2, 0.9 Hz), 7.09 (1H,t, J=7.2 Hz), 8.13 (1H, br s).

Following compounds were obtained, according to the similar treatment.

Compd m.p. No R⁷ (° C.) ¹H-NMR (CDCl₃) 7-2 Ph 188-189 1.38 (9H, s), 3.18(1H, m), 3.43 (1H, m), 4.29 (1H, d, J=12.0 Hz), 4.39 (1H, m), 4.56 (1H,m), 5.08 (1H, br s), 6.70 (1H, m), 7.04 (1H, m), 7.11 (1H, t, J=7.8 Hz),7.34-7.55 (5H, m), 8.28 (1H, br s)

Example 5 2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[c,d]azulen-8-ylamine (8-1)

The compound obtained in Ex 4 (7-1) 262 mg was dissolved in ethylacetate 3 ml. A solution of 4 N HCl/ethyl acetate 2 ml was added to thesolution with cooling in ice and the mixture was stirred at roomtemperature for 3 h. Furthermore, 4N-HCl/ethyl acetate 1 ml was addedand the mixture was stirred at room temperature for 1 h. After thevolatile materials were remove by distillation under reduced pressure upto the half volume, the mixture was diluted with ethyl acetate 10 ml. Anaqueous saturated sodium hydrogen solution carbonate was added toalkaline with cooling in ice. The mixture was extracted with ethylacetate. The extracts were washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to give abrown oily residue, which was chromatographed on aluminum oxide 40 g inmethanol:chloroform (3:97) to give the titled compound (8-1) as browncrystals, 144 mg. Yield 84%.

Further, this oil was recrystallized from isopropanol to give the titledcompound (8-1) as gray crystals, 60 mg. m.p. 172-173° C.

¹H-NMR (CD₃OD): 2.84-2.93 (1H, ddd, J=15.6, 8.7, 1.5 Hz), 3.17-3.25 (1H,m), 3.36-3.43 (1H, m), 4.12-4.25 (2H, m), 6.43-6.50 (1H, m), 6.89-7.00(3H, m).

Following compounds were obtained, according to the similar treatment.

Compd m.p. No R⁷ (° C.) ¹H-NMR (CDCl₃) 8-2 Ph 189-191 3.09 (1H, dd,J=15.6, 8.1 Hz), 3.29 (1H, dd, J=15.6, 3.6 Hz), 3.59 (1H, m), 4.27-4.36(2H, m), 6.67 (1H, m), 7.01 (1H, m), 7.10 (1H, t, J=8.1 Hz), 7.34-7.59(5H, m), 8.25 (1H, br s)

Scheme of Reactions, Examples 6-10 are shown in below

Example 68-Hydroxy-2,7-dihydro-6-oxa-2-azabenzo[c,d]azulene-9-carbonitrile (10)

Compound (9) 200 mg was dissolved in dry tetrahydrofuran 10 ml. 60%Sodium hydride 72 mg was added to the solution with cooling in ice andthe mixture was stirred at room temperature for 2.5 h. After excesssodium hydride was decomposed with ethanol with cooling in ice, 2 N—HCl1.5 ml was added. The mixture was extracted with ether. The extractswere washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschromatographed on silica gel 4 g in ether to give an eluent 187 mgwhich was again chromatographed on silica gel 5 g in ether to give thetitled compound (10) as reddish orange crystals, 132 mg. Yield 79.5%.

¹H-NMR (CDCl₃): 4.80 (2H, s), 6.52 (1H, dd, J=7.5, 0.9 Hz), 6.99 (1H, t,J=7.5 Hz), 7.06 (1H, dd, J=7.5, 0.9 Hz), 7.24 (1H, d, J=2.7 Hz), 11.07(1H, s), 11.39 (1H, s).

Example 7 (1) 3-Ethoxycarbonylmethyl-1H-indol-4-yloxy)acetic acid ethylester (11)

Compound (9) 1.49 g was dissolved in 95% ethanol 45 ml. Concentratedsulfuric acid 4.5 ml was added to the solution. The mixture was heatedunder reflux for 40 h. After the solvent was removed under reducedpressure, ice-water was added to the mixture, which was extracted withchloroform. The extracts were washed with water dried over anhydrousmagnesium sulfate and chromatographed on silica gel 37 g in chloroform.The eluent 1.497 g was recrystallized from acetone-isopropyl ether togive the titled compound (11) as pale gray crystals, 1.304 g, m.p.90-91.5° C. Yield 70.1%.

¹H-NMR (CDCl₃): 1.26 (3H, t, J=7.2 Hz), 1.31 (3H, t, J=7.2 Hz), 4.05(2H, s), 4.18 (2H, q, J=7.2 Hz), 4.28 (2H, q, J=7.2 Hz), 4.69 (2H, s),6.36 (1H, dd, J=7.2, 0.9 Hz), 6.97-7.07 (3H, m), 8.07(1H, br s).

(2) 8-Hydroxy-2,7-dihydro-6-oxa-2-azabenzo[c,d]azulene-9-carboxylic acidethyl-ester (12)

Compound (11) 754 mg was dissolved in dry tetrahydrofuran 20 ml. 60%Sodium hydride 217 mg was added to the solution of with cooling in ice.The mixture was stirred at room temperature for 1 h. To the ice-coldreaction mixture, ethanol 0.5 ml was added and the 2N HCl 3 ml was addedto acidify. The mixture was extracted with ether. The extracts werewashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschromatographed on silica gel 45 g in chloroform. The eluent 198 mg wasrecrystallized from ether-isopropyl ether to give the titled compound(12) as colorless crystals 195 mg, m.p. 136-137° C. Yield 30.5%.

¹H-NMR (CDCl₃): 1.44 (3H, t, J=7.2 Hz), 4.42 (2H, q, J=7.2 Hz), 4.75(2H, s), 6.56-6.71 (1H, m), 7.02-7.09 (2H, m), 7.50 (1H, d, J=2.7 Hz),8.20 (1H, br s), 13.02 (1H, s).

Example 88-Methoxyl-2,7-dihydro-6-oxa-2-azabenzo[c,d]azulene-9-carboxylic acidethyl ester (13)

A mixture of the compound obtained in Ex. 7 (12) 100 mg, methyl iodide0.031 ml and potassium carbonate 9 mg in dimethylformamide 3 ml wasstirred at room temperature for 15 h. Water was added and the mixturewas extracted with ether. The extracts were washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue obtained was chromatographed on silica gel 6 g inchloroform. The eluent 102 mg was recrystallized from acetone-ether togive the titled compound (13) as colorless crystals 67 mg, m.p. 183-184°C. Yield 63.8%.

¹H-NMR (CDCl₃): 1.24-1.29 (3H, m), 1.82 (3H, s), 4.16-4.35 (2H, m), 4.49(1H, d, J=17.4 Hz), 5.02 (1H, d, J=17.4 Hz), 6.73-6.79 (1H, m),6.96-6.97(1H, m), 7.02-7.13 (2H, m), 8.35 (1H, br s).

Example 9 (1)4-Ethoxycarbonylmethoxy-3-ethoxycarbonylmethyl-indole-1-carboxylic acidtert-butyl ester (14)

Compound (11) 1.40 g and di-tert-butyldicarbonate 1.05 g were dissolvedin tetrahydrofuran 20 ml and 4-dimethylaminopyridine 28 mg was added.The mixture was allowed to stand at room temperature overnight andconcentrated under reduced pressure to remove tetrahydrofurane. Theresidue obtained was dissolved in toluene and chromatographed on silicagel 10 g in 5% ethyl acetate-toluene to give the titled compound (14) asa colorless oil, 1.789 g. Yield 96.2%.

¹H-NMR (CDCl₃): 1.26 (3H, t, J=7.2 Hz), 1.30 (3H, t, J=7.2 Hz), 1.65(9H, s), 3.96 (2H, s), 4.18 (2H, q, J=7.2 Hz), 4.27 (2H, q, J=7.2 Hz),4.67 (2H, s), 6.52 (1H, d, J=8.1 Hz), 7.18 (1H, t, J=8.1 Hz), 7.42 (1H,s), 7.80 (1H, d, J=8.1 Hz).

(2) 8-Hydroxy-7H-6-oxa-2-azabenzo[c,d]azulene-2,9-dicarboxlic acid2-tert-butyl ester 9-ethyl ester (15)

Compound (14) 953 mg was dissolved in dry tetrahydrofuran 15 ml and 1.0M solution of lithium bistrimethylsilylamide-tetrahydrofuran 3.5 ml wasadded to the solution with cooling in ice. The mixture was stirred atroom temperature for 30 min. A solution of ammonium chloride 375 mg inwater 5 ml was added with cooling in ice. The mixture was extracted withether. The extracts were washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residueobtained was chromatographed on silica gel 30 g in chloroform. Theeluent 259 mg was recrystallized from ether-isopropyl ether to give thetitled compound (15) as colorless crystals, m.p.139.5-140.5° C., 236 mg.Yield 28.0%.

¹H-NMR (CDCl₃): 1.47 (3H, t, J=7.1 Hz), 1.68 (9H, s), 4.43 (2H, q, J=7.1Hz), 4.73 (2H, s), 6.80 (1H, d, J=8.1 Hz), 7.18 (1H, t, J=8.1 Hz), 7.83(1H, d, J=8.1 Hz), 7.87 (1H, s), 13.27 (1H, s).

Example 10 (1)[3-Ethoxycarbonylmethyl-1-(toluene-4-sulfonyl)-1H-indol-4-yloxy]aceticacid ethyl ester (16)

Compound (11) 305 mg was dissolved in dry tetrahydrofuran 20 ml. 1.0 MSolution of lithium bistrimethylsilylamide-tetrahydrofuran 1.1 ml wasadded to the solution with cooling in dry ice-acetone bath at −70° C.After the mixture was stirred for 10 min, a solution ofp-toluenesulfonyl chloride 229 mg in tetrahydrofuran 3 ml was added atthat temperature. The mixture was stirred at room temperature for 2 h. Asolution of ammonium chloride 59 mg in water 1 ml was added to themixture, which was concentrated under reduced pressure to removetetrahydrofuran. Water was added. The mixture was extracted withchloroform. The extracts were washed with water dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residueobtained was chromatographed on silica gel 17 g in chloroform to givethe titled compound (16) as a colorless oil 231 mg. Yield 50.2%.

¹H-NMR (CDCl₃): 1.24 (3H, t, J=7.2 Hz), 1.28 (3H, t, J=7.2 Hz), 2.34(3H, s), 3.94 (2H, s), 4.16 (2H, q, J=7.2 Hz), 4.25 (2H, q, J=7.2 Hz),4.62 (2H, s), 6.49 (1H, d, J=8.1 Hz), 7.17 (1H, t, J=8.1 Hz), 7.21 (2H,d, J=8.7 Hz), 7.44 (2H, d, J=8.7 Hz), 7.60 (1H, d, J=8.1 Hz), 7.74 (2H,d, J=8.7 Hz).

(2)8-Hydroxy-2-(toluene-4-sulfonyl)-2,7-dihydro-6-oxa-2-azabenzo[c,d]-azulene-9-carboxlicacid ethyl ester (17)

Compound (16) 228 mg was dissolved in dry tetrahydrofuran 10 ml and 1.0M solution of lithium bistrimethylsilylamide tetrahydrofuran 1.05 ml wasadded to the solution with cooling in ice. The mixture was stirred for20 min. A solution of ammonium chloride 112 mg in water 1 ml was addedto the mixture, which was acidified with dilute hydrochloric acid. Themixture was extracted with ether. The extracts were washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue obtained 279 mg was chromatographed on silica gel10 g in toluene to give the titled compound (17) as a pale yellow oil 61mg. Yield 29.8%.

¹H-NMR (CDCl₃): 1.50 (3H, t, J=7.2 Hz), 2.35 (3H, s), 4.45 (2H, q, J=7.2Hz), 4.68 (2H, s), 6.78 (1H, dd, J=7.8, 0.9 Hz), 7.17 (1H, t, J=7.8 Hz),7.23 (2H, d, J=8.1 Hz), 7.67 (1H, dd, J=7.8, 0.9 Hz), 7.77 (2H, d, J=8.7Hz) 7.80 (1H, s), 13.30 (1H, s).

Scheme of Reactions, Examples 11-16

Example 11 2,9-Dihydro-6-oxa-2-azabenzo[cd]azulen-8-one (18-1)(R⁷═R¹¹═H)

Triethylamine 10 ml and ethyl chlorocarbonate 5.6 ml were added to asolution of compound (5-1) 14.85 g in dry tetrahydrofuran 148 ml withcooling in ice-methanol bath. The mixture was stirred at thattemperature for 30 min. Then, a solution sodium azide 8.97 g in water 59ml was added dropwise. The mixture was stirred with cooling in ice for 4h. To the reaction mixtures water was added. The mixture was extractedwith ethyl acetate. The extracts were washed with brine, dried overanhydrous magnesium sulfate, concentrated under reduced pressure to givea yellow solid. The residue obtained was suspended in dioxane 280 ml.After the suspension was heated under reflux for 20 min, 1N HCl 58.3 mlwas added with cooling in ice. Again, the mixture was heated underreflux for 20 min and cooled in ice-bath. Water was added. The mixturewas extracted with ether. The extracts were washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue obtained was chromatographed on silica gel 150 gin ethyl acetate:hexane (1:4) to give brown crystals, which wasrecrystallized from ether-petroleum ether to give the titled compound7.94 g, m.p. 128-129° C. Yield 61%.

¹H-NMR(CDCl₃): 4.11 (2H, d, J=0.6 Hz), 4.69 (2H, s), 6.72-6.79 (1H, m),6.92-6.95 (1H, m), 7.07-7.14 (2H, m), 8.12 (1H, br s).

Following compounds were obtained, according to the similar treatment.

Compd m.p. No R⁷ R¹¹ (° C.) ¹H-NMR (CDCl₃) 18-2 Me ME 136-139 2.32 (3H,s), 2.33 (3H, s), 3.99 (2H, s), 4.66 (2H, s), 6.89 (1H, d, J=8.4 Hz),6.92 (1H, d, J=8.4 Hz), 7.77 (1H, br s) 18-3 H Br 137-138 4.09 (2H, d,J=1.2 Hz), 4.75 (2H, s), 6.95 (1H, m), 7.01 (1H, d, J=8.7 Hz), 7.27 (1H,d, J=8.7 Hz), 8.14 (1H, br s)

Example 12Dimethyl-(2,7,8,9-tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-yl)amine(19-1) (R⁷═R¹¹═H; R¹⁶═R¹⁷═Me)

Dimethylamine (2 mol/tetrahydrofuran solution), compound (18-1) 690 mg,sodium triacetoxyborohydride 1.17 g and acetic acid 226 mg weredissolved in tetrahydrofuran 28 ml with cooling in ice. The mixture wasstirred at room temperature for 1 h and allowed stand overnight. To thereaction mixture, ice-water and an aqueous sodium hydrogen carbonatesolution were added. The mixture was extracted with ether. The extractswere washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschromatographed on aluminum oxide 30 g in chloroform:methanol (50:1) togive the titled compound as colorless crystals 689 mg. Yield 86%. Thiswas recrystallized from ethyl acetate-hexane to give colorless crystals,m.p. 131-132.5° C.

¹H-NMR(CDCl₃): 2.42 (6H, s), 2.93-3.24 (3H, m), 4.15 (1H, dd, J=12.3,6.6 Hz), 4.55 (1H, dd, J=12.3, 1.5 Hz), 6.62 (1H, dd, J=6.6, 0.9 Hz),6.95-7.09 (3H, m), 8.14 (1H, br s).

Following compounds were obtained, according to the similar treatment.

Compd No R⁷ R¹¹ R¹⁶ R¹⁷ m.p. (° C.) ¹H-NMR (CDCl₃) 19-2 H H H Me 112-1162.56 (3H, s), 2.99-3.22 (3H, m), oxalate 4.27-4.38 (2H, m), 6.65 (1H, d,J= 7.5 Hz), 6.96-7.09 (3H, m), 8.24 (1H, br s) 19-3 H H H nPr 137-1390.93 (3H, t, J=7.5 Hz), 1.54 (2H, sex, J=7.5 Hz), 2.62-2.80 (2H, m),2.92-3.02 (1H, m), 3.14-3.25 (2H, m), 4.19-4.30 (2H, m), 6.44-6.50 (1H,m), 6.90-7.02 (3H, m) CD₃OD 19-4 H H Et Et 123-124 1.12 (6H, t, J=7.5Hz), 2.69 (4H, q, J=7.5 Hz), 2.90-3.00 (1H, m), 3.20-3.30 (2H, m), 4.08(1H, dd, J= 11.7, 6.3 Hz), 4.53 (1H, dd, J= 11.7, 2.1 Hz), 6.41-6.48(1H, m), 6.88-6.95 (2H, m), 7.01-7.03 (1H, m) CD₃OD 19-5 H H NPr nPr60-61 0.90 (6H, t, J=7.5 Hz), 1.40-1.60 (4H, m), 2.40-2.60 (4H, m),2.90- 3.01 (1H, m), 3.15-3.35 (2H, m), 4.09 (1H, dd, J=12.3, 6.9 Hz),4.61 (1H, dd, J=12.3, 1.8 Hz), 6.61 (1H, d, J=7.5 Hz), 6.95-6.98 (2H,m), 7.06 (1H, t, J=7.5 Hz), 8.06 (1H, br s) 19-6 H H H cyclohexyl141-142 1.00-2.02 (10H, m), 2.64-2.74 (1H, m), 2.98 (1H, ddd, J=15.3,8.4, 1.2 Hz), 3.14 (1H, dd, J=15.3, 3.6 Hz), 3.39-3.47 (1H, m),4.23-4.32 (2H, m), 6.63 (1H, dd, J=7.5, 0.9 Hz), 6.95-6.99 (2H, m), 7.07(1H, t, J=7.5 Hz), 8.11 (1H, br s) 19-7 H H H allyl 112-113 3.00-3.18(2H, m), 3.28-3.49 (1H, m), 4.27-4.38 (2H, m), 5.08-5.13 (1H, m),5.18-5.26 (1H, m), 5.86- 5.99 (1H, m), 6.64 (1H, dd, J= 7.8, 1.2 Hz),6.95-7.00 (2H, m), 7.07 (1H, t, J=7.8 Hz), 8.11 (1H, br s) 19-8 H H HiPr 133-135 1.10 (3H, d, J=6.0 Hz), 1.11 (3H, d, J=6.0 Hz), 2.97-3.17(3H, m), 3.35-3.42 (1H, m), 4.25-4.37 (2H, m), 6.64 (1H, dd, J=7.5, 0.9Hz), 6.95-7.00 (2H, m), 7.07 (1H, t, J=7.5 Hz), 8.10 (1H, br s) 19-9 H HH

104-106 2.83 (2H, t, J=7.5 Hz), 2.95-3.17 (4H, m), 3.26-3.33 (1H, m),4.29 (2H, d, J=3.6 Hz), 6.62 (1H, d, J= 7.5 Hz), 6.93-7.00 (2H, m), 7.07(1H, t, J=7.8 Hz), 7.18-7.30 (5H, m), 8.08 (1H, br s) 19-10 H H

137-139 1.80-1.89 (4H, m), 2.70-3.04 (6H, m), 3.37(1H, d, J=14.4 Hz),4.17 (1H, dd, J=12.3, 6.3 Hz), 4.59 (1H, dd, J=12.3, 2.1 Hz), 6.61 (1H,dd, J=7.5, 0.9 Hz), 6.95-6.99 (2H, m), 7.06 (1H, t, J=7.8 Hz), 8.10 (1H,br s) 19-11 H H

115-125 (dec.) oxalate 1.45-1.75 (6H, m), 2.50-2.80 (4H, m), 2.94-3.12(2H, m), 3.24-3.31 (1H, m), 4.10 (1H, dd, J=12.0, 6.3 Hz), 4.63 (1H, dd,J=12.0, 1.8 Hz), 6.61 (1H, dd, J=7.8, 0.9 Hz), 6.94-6.98 (2H, m), 7.06(1H, t, J= 7.8 Hz), 8.10 (1H, br s) 19-12 H H

183-184 (dec.) oxalate 2.32 (3H, s), 2.40-2.60 (4H, m), 2.62-2.73 (2H,m), 2.80-2.90 (2H, m), 2.95-3.11 (2H, m), 3.22-3.30 (1H, m), 4.12 (1H,dd, J=12.3, 6.3 Hz), 4.60 (1H, dd, J=12.3, 2.1 Hz), 6.61 (1H, dd, J=7.8,0.9 Hz), 6.95-6.99 (2H, m), 7.06 (1H, t, J= 7.8 Hz), 8.12 (1H, br s)19-13 H H

207-208 2.46-2.56 (2H, m), 2.62-2.72 (2H, m), 2.76-2.98 (2H, m),3.08-3.18 (1H, m), 3.53-3.62 (4H, m), 4.06 (1H, dd, J=12.3, 6.6 Hz),4.45 (1H, d, J=12.3 Hz), 6.40 (1H, dd, J=6.6, 2.1 Hz), 6.86-6.94 (2H,m), 7.11 (1H, d, J=1.8 Hz), 10.95 (1H, br s) DMSO-d₆ 19-14 H H HCH₂CH₂OH 154-157 2.85-3.11 (4H, m), 3.25-3.30 (2H, (dec.) m), 3.62 (2H,t, J=5.4 Hz), 4.26- oxalate 4.42 (2H, m), 6.64 (1H, dd, J=7.5, 0.9 Hz),6.96-7.10 (3H, m), 8.16 (1H, br s) 19-15 H Br H Me 2.58 (3H, s),2.91-3.22 (3H, m), 4.34(1H, dd, J=12.6, 6.9 Hz), 4.44(1H, d, J=12.6 Hz),6.86 (1H, d, J=8.4 Hz), 6.97 (1H, m), 7.28 (1H, d, J=8.4 Hz), 8.17 (1H,br s) 19-16 H Br Me Me 142-143 2.43 (6H, s), 2.92-3.23 (3H, m), 4.22(1H, dd, J=12.3, 6.9 Hz), 4.67 (1H, dd, J=12.3, 1.8 Hz), 6.85 (1H, d,J=8.7 Hz), 6.98 (1H, m), 7.26 (1H, d, J=8.7 Hz), 8.13 (1H, br s) 19-17Me Me Me Me 144-146 2.28 (3H, s), 2.34 (3H, s), 2.47 (6H, s), 2.82-3.11(3H, m), 4.10 (1H, dd, J=12.0 Hz, 6.6 Hz), 4.58 (1H, d, J=12.0 Hz), 6.79(1H, d, J=8.1 Hz), 6.87 (1H, d, J=8.1 Hz), 7.74 (1H, br s) 19-18 Me Me HMe 173-175 2.29 (3H, s), 2.31 (6H, s), 2.57 (3H, (dec.) s), 2.80-2.87(1H, m), 2.97-3.03 oxalate (1H, m), 3.12-3.20 (1H, m), 4.29- 4.32 (2H,m), 6.79 (1H, d, J=8.1 Hz), 6.87 (1H, d, J=8.1 Hz), 7.79 (1H, br s),19-19 H H H cyclopropyl 130-131 0.34-0.55 (4H, m), 2.27-2.34 (1H, m),3.02-3.18 (2H, m), 3.38-3.44 (1H, m), 4.33-4.44 (2H, m), 6.65 (1H, dd,J=7.5, 0.9 Hz), 6.94-7.07 (3H, m), 8.27 (1H, br s) 19-20 H H H CH₂CF₃108-109 3.13 (2H, d, J=5.1 Hz), 3.27-3.44 (3H, m), 4.25 (1H, d, J=12.6Hz), 4.40 (1H, dd, J=12.6, 6.9 Hz), 6.64 (1H, dd, J=8.1, 0.9 Hz), 6.98(1H, s), 7.00 (1H, dd, J=8.1, 0.9 Hz), 7.08 (1H, t, J=8.1 Hz), 8.10 (1H,br s) 19-21 H H Me Et 122-124 1.13 (3H, t, J=7.2 Hz), 2.39 (3H, s),2.54-2.79 (2H, m), 2.97-3.27 (3H, m), 4.12 (1H, dd, J=12.3, 6.3 Hz),4.59 (1H, dd, J=12.3, 1.8 Hz), 6.62 (1H, dd, J=7.5, 0.9 Hz), 6.96-7.09(3H, m), 8.12 (1H, br s) 19-22 H H H Et 139-141 1.14 (3H, t, J=7.2 Hz),2.73-2.93 (2H, m), 3.00-3.19 (2H, m), 3.26- 3.33 (1H, m), 4.27-4.37 (1H,m), 6.64 (1H, dd, J=7.5, 0.9 Hz), 6.96-6.99 (2H, m), 7.07 (1H, t, J= 7.5Hz), 8.15 (1H, br s)

Example 13

(Method 1)

(2-Benzenesulfonyl-2,7,8,9-tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-yl)dimethylamineoxalate (20-1) (R⁷═R¹¹═H)

60% Sodium hydride 17 mg was added to a solution of compound (19-1) 75mg in dry dimethylformamide 2.5 ml with cooling in ice. The mixture wasstirred at 45° C. for 1 h. Benzenesulfonyl chloride 1 ml was added withcooling in ice. The mixture was stirred at room temperature for 21 h.Ice-water and an aqueous sodium hydrogen carbonate solution were addedto the mixture, which was extracted with ether. The extracts were washedwith brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue obtained was chromatographed onaluminum oxide in chloroform:hexane (1:2) to give the titled compound,46 mg (yield 37%). This compound was treated with 1 eq. of oxalic acidto give the oxalic acid salt, which was recrystallized fromether-ethanol to give colorless crystals. m.p. 106-109° C.(dec.).

¹H-NMR(CDCl₃): 2.36 (6H, s), 2.80-3.12 (3H, m), 4.13 (1H, dd, J=12.3,6.6 Hz), 4.42 (1H, dd, J=12.3, 0.6 Hz), 6.75 (1H, d, J=8.1 Hz),7.14-7.20 (1H, m), 7.34 (1H, s), 7.41-7.61 (4H, m), 7.86-7.89 (2H, m)

Following compounds were obtained, according to the similar treatment.

Comp No. R⁷ R⁸ R¹¹ m.p. ¹H-NMR (CDCl₃) 20-2 H COPh H 126-129 2.40 (6H,s), 2.86-3.16 (3H, m), 4.20 (1H, (dec.) dd, J=12.3, 6.3 Hz), 4.50 (1H,d, J= oxalate 12.3 Hz), 6.85 (1H, dd, J=7.2, 0.9 Hz), 7.06 (1H, s),7.23-7.28 (1H, m), 7.49-7.63 (3H, m), 7.71 (2H, dd, J=8.4, 1.8 Hz), 8.04(1H, dd, J=8.1, 0.9 Hz) 20-3 H CH₂Ph H 183-186 2.41 (6H, s), 2.88-3.06(2H, m), 3.15-3.22 (dec.) (1H, m), 4.15 (1H, dd, J=12.0, 6.3 Hz),oxalate 4.54 (1H, dd, J=12.0, 1.8 Hz), 5.23 (2H, s) 6.61 (1H, dd, J=7.8,0.6 Hz), 6.85- 6.89 (2H, m), 7.02-7.15 (3H, m), 7.25- 7.33 (3H, m) 20-4H CH₂CONMe₂ H 119-124 2.40 (6H, s), 2.99 (3H, s), 3.04 (3H, s), (dec.)2.88-3.22 (2H, m), 3.15-3.22 (1H, m), oxalate 4.13 (1H, dd, J=12.3, 6.6Hz), 4.53 (1H, dd, J=12.3, 1.8 Hz), 4.82 (2H, s), 6.61 (1H, dd, J=8.1,0.9 Hz), 6.79-7.10 (3H, m) 20-5 H

H 148-149 2.37 (6H, s), 2.89 (1H, m), 3.06-3.16 (2H, m), 4.15 (1H, dd,J=12.9, 6.9 Hz), 4.43 (1H, d, J=12.9 Hz), 6.71 (1H, dd, J= 7.8, 0.6 Hz),7.10 (1H, t, J=8.1 Hz), 7.39-7.67 (5H, m), 7.86-8.15 (3H, m), 8.76 (1H,d, J=8.7 Hz) 20-6 H

H 114-118 (dec.) oxalate 2.36 (6H, s), 2.81-3.11 (3H, m), 4.14 (1H, dd,J=12.6, 6.6 Hz), 4.43 (1H, d, J= 12.6 Hz), 6.76 (1H, dd, J=7.8, 0.9 Hz),7.18 (1H, t, J=8.4 Hz), 7.23 (1H, t, J= 1.5 Hz), 7.38-7.42 (2H, m), 7.57(1H, dd, J=8.4, 0.9 Hz), 7.77-7.82 (2H, m) 20-7 H SO₂Et H 153-155 1.23(3H, t, J=7.5), 2.41 (6H, s), 2.87- (dec.) 3.14 (3H, m), 3.28 (3H, q,J=7.5 Hz), oxalate 4.22 (1H, dd, J=12.3, 6.6 Hz), 4.49 (1H, d, J=12.3Hz), 6.82 (1H, d, J=7.8 Hz), 7.19-7.27 (2H, m), 7.50 (1H, J=8.4 Hz) 20-8H IPr H 191-194 1.49 (3H, t, J=6.3 Hz), 1.50 (3H, t, J= (dec.) 6.3 Hz),2.42 (6H, s), 2.93-3.24 (3H, m), oxalate 4.13 (1H, dd, J=12.3, 6.6 Hz),4.54 (1H, dd, J=12.3, 1.8 Hz), 4.57-4.66 (1H, m), 6.59 (1H, dd, J=7.8,1.2 Hz), 6.94 (1H, d, J=7.5 Hz), 7.01 (1H, s), 7.07 (1H, d, J= 7.8 Hz)20-9 H

H 142-144 (dec.) oxalate 2.37 (6H, s), 2.81-3.10 (3H, m), 4.16 (1H, dd,J=12.3, 6.6 Hz), 4.43 (1H, dd, J= 12.3 Hz), 6.78 (1H, d, J=8.4 Hz), 7.00(1H, dd, J=4.8, 3.9 Hz), 7.21 (1H, t, J= 8.4 Hz), 7.30 (1H, s), 7.53(1H, dd, J= 5.1, 1.5 Hz), 7.62 (1H, d, J=8.4 Hz), 7.67 (1H, dd, J=4.2,1.5 Hz) 20-10 H

H 119-122 (dec.) oxalate 2.37 (6H, s), 2.82-2.88 (1H, m), 2.96-3.11 (2H,m), 4.16 (1H, dd, J=12.6, 6.6 Hz), 4.43 (1H, d, J=12.6 Hz), 6.78 (1H,dd, J= 8.1, 0.9 Hz), 7.17-7.32 (2H, m), 7.59 (1H, dd, J=8.1, 0.6 Hz),7.71 (2H, d, J= 8.4 Hz), 8.00 (2H, d, J=8.1 Hz) 20-11 H

H 147-150 (dec.) oxalate 2.37 (6H, s), 2.82-3.12 (3H, m), 4.14 (1H, dd,J=12.6, 6.6 Hz), 4.43 (1H, d, J= 12.6 Hz), 6.77 (1H, dd, J=7.8, 0.6 Hz),7.18 (1H, t, J=8.1 Hz), 7.30 (1H, s), 7.55-7.58 (2H, m), 7.71-7.74 (2H,m) 20-12 H

H 168-171 (dec.) oxalate 2.37 (6H, s), 2.81-3.11 (3H, m), 4.16 (1H, dd,J=12.3, 6.6 Hz), 4.42 (1H, d, J= 12.3 Hz), 6.77 (1H, dd, J=8.1, 0.3 Hz),7.20 (1H, t, J=8.1 Hz), 7.30-7.34 (2H, m), 7.57 (1H, d, J=8.1 Hz),7.64-7.81 (2H, m), 8.01 (1H, t, J=1.8 Hz) 20-13 H

H 173-176 (dec.) oxalate 2.40 (6H, s), 2.86-3.11 (3H, m), 4.21 (1H, dd,J=12.3, 6.6 Hz), 4.60 (1H, d, J= 12.3 Hz), 6.75 (1H, dd, J=8.1, 0.6 Hz),7.09 (1H, t, J=8.1 Hz), 7.23-7.26 (1H, m), 7.36-7.50 (2H, m), 7.55 (1H,s), 7.67 (1H, dd, J=7.8, 1.5 Hz), 8.09 (1H, dd, J=7.8, 1.5 Hz) 20-14 H

H 140-142 (dec.) oxalate 2.37 (6H, s), 2.81-3.11 (3H, m), 3.80 (3H, s),4.13 (1H, dd, J=12.3, 6.6 Hz), 4.43 (1H, d, J=12.3 Hz), 6.74 (1H, d,J=8.1 Hz), 6.88 (2H, dd, J=6.9, 2.1 Hz), 7.17 (1H, t, J=8.4 Hz), 7.33(1H, s), 7.58 (1H, d, J=8.1 Hz), 7.82 (1H, dd, J=6.9, 2.1 Hz) 20-15 H

H 123-126 (dec.) oxalate 2.37 (6H, s), 2.82-3.11 (3H, m), 3.85 (3H, s),3.87 (3H, s), 4.14 (1H, dd, J=12.3, 5.7 Hz), 4.44 (1H, d, J=12.3 Hz),6.75 (1H, dd, J=7.8, 0.9 Hz), 6.84 (2H, d, J= 8.7 Hz), 7.17 (1H, t,J=8.1 Hz), 7.26- 7.32 (2H, m), 7.51 (1H, dd, J=8.4, 2.1 Hz), 7.61 (1H,dd, J=8.4, 0.6 Hz) 20-16 H

H 169-171 (dec.) oxalate 2.39 (6H, s), 2.85-3.13 (3H, m), 4.19 (1H, dd,J=12.6, 6.3 Hz), 4.46 (1H, d, J= 12.6 Hz), 6.74 (1H, d, J=15.3 Hz), 6.80(1H, dd, J=8.4, 0.6 Hz), 7.20 (1H, t, J= 8.4 Hz), 7.27-7.45 (6H, m),7.52 (1H, dd, J=8.1, 0.9 Hz), 7.70 (1H, d, J=15.5 Hz) 20-17 H

H 161-163 (dec.) oxalate 2.39 (6H, s), 2.84-3.09 (3H, m), 4.21 (1H, dd,J=12.3, 5.4 Hz), 4.44 (1H, d, J= 12.3 Hz), 6.77 (1H, dd, J=8.4, 0.9 Hz),7.13 (1H, t, J=8.4 Hz), 7.25 (1H, dd, J= 8.1, 0.9 Hz), 7.35 (1H, d,J=8.4 Hz), 7.43-7.48 (2H, m), 8.19 (1H, d, J=2.4 Hz) 20-18 H SO₂Ph Br89-90 2.39 (6H, s), 2.85-3.10 (3H, m), 4.24 (1H, dd, J=12.3, 6.3 Hz),4.54 (1H, d, J= 12.3 Hz), 7.34 (1H, s), 7.39-7.59 (5H, m), 7.84-7.87(2H, m) 20-19 H

H 143-144 (dec.) oxalate 2.37 (6H, s), 2.82-2.88 (1H, m), 2.96-3.11 (2H,m), 4.15 (1H, dd, J=12.6, 6.6 Hz), 4.42 (1H, d, J=12.6 Hz), 6.76 (1H, d,J= 7.8 Hz), 7.08-7.21 (3H, m), 7.25 (1H, dd, J=8.1, 0.9 Hz), 7.31 (1H,s), 7.56 (1H, d, J=8.4 Hz), 7.87-7.92 (2H, m) 20-20 H

H 128-131 (dec.) oxalate 2.40 (6H, s), 2.85-2.91 (1H, m), 3.07-3.10 (2H,m), 4.21 (1H, dd, J=12.6, 6.6 Hz), 4.44 (1H, d, J=12.6 Hz), 6.79 (1H,dd, J= 8.1, 0.9 Hz), 7.12 (1H, t, J=8.1 Hz), 7.33-7.42 (3H, m), 7.78(1H, dd, J=7.2, 6.0 Hz) 20-21 H

H 154-156 (dec.) oxalate 2.38 (6H, s), 2.83-3.13 (3H, m), 4.18 (1H, dd,J=12.6, 6.6 Hz), 4.44 (1H, d, J= 12.6 Hz), 6.80 (1H, dd, J=8.1, 0.6 Hz),6.83 (1H, d, J=4.2 Hz), 7.19-7.25 (2H, m), 7.46 (1H, d, J=4.1 Hz), 7.56(1H, dd, J=8.1, 0.6 Hz) 20-22 H

H 163-164 (dec.) oxalate 2.38 (6H, s), 2.82-3.09 (3H, m), 4.19 (1H, dd,J=12.3, 6.3 Hz), 4.44 (1H, d, J= 12.3 Hz), 6.75-7.03 (3H, m), 7.13 (1H,t, J=8.1 Hz), 7.38-7.41 (2H, m), 8.02-8.11 (1H, m) 20-23 H

H 147-150 (dec.) oxalate 2.39 (6H, s), 2.84-3.10 (3H, m), 3.66 (3H, s),3.82 (3H, s), 4.18 (1H, dd, J=12.3, 6.6 Hz), 4.44 (1H, d, J=12.3 Hz),6.72 (1H, dd, J=8.1, 0.9 Hz), 6.81 (1H, d, J= 9.0 Hz), 7.04 (1H, dd,J=9.0, 3.3 Hz), 7.09 (1H, t, J=8.1 Hz), 7.36 (1H, d, J= 8.1 Hz), 7.43(1H, s), 7.60 (1H, d, J=3.3 Hz) 20-24 H

H 103-104 2.37 (6H, s), 2.82-3.12 (3H, m), 3.79 (3H, s), 3.82 (3H, s),4.15 (1H, dd, J=12.6, 6.6 Hz), 4.43 (1H, d, J=12.6 Hz), 6.75 (1H, dd,J=8.1, 0.6 Hz), 7.03-7.07 (1H, m), 7.17 (1H, t, J=8.1 Hz), 7.31-7.46(4H, m), 7.60 (1H, dd, J=8.1, 0.6 Hz) 20-25 H

H 113-115 (dec.) oxalate 2.32 (6H, s), 2.81-3.12 (3H, m), 4.17 (1H, dd,J=12.6, 6.3 Hz), 4.44 (1H, d, J= 12.6 Hz), 6.46 (1H, d, J=1.8 Hz), 6.80(1H, d, J=7.8 Hz), 7.24 (1H, t, J=8.1 Hz), 7.29 (1H, d, J=3.9 Hz), 7.33(1H, d, J=3.9 Hz), 7.61 (1H, d, J=7.8 Hz), 7.64 (1H, d, J=3.9 Hz), 8.27(1H, d, J =1.8 Hz) 20-26(*) H SO₂Ph H 98-98 1.09 (3H, t, J=7.2 Hz), 2.34(3H, s), (dec.) 2.50-2.74 (2H, m), 2.91-3.16 (3H, m), oxalate 4.05 (1H,dd, J=12.0, 6.6 Hz), 4.51 (1H, dd, J=12.0, 0.9 Hz), 6.74 (1H, dd, J=8.1, 0.6 Hz), 7.17 (1H, t, J=8.1 Hz), 7.34 (1H, s), 7.41-7.61 (5H, m),7.86- 7.89 (2H, m) 20-27 Me SO₂Ph Me 155-158 2.24 (3H, s), 2.39 (6H, s),2.52 (3H, s), (dec.) 4.05 (1H, dd, J=12.6, 5.7 Hz), 4.46 (1H, oxalate d,J=12.6 Hz), 7.01 (1H, d, J=8.7 Hz), 7.38-7.43 (2H, m), 7.49-7.55 (1H,m), 7.71-7.77 (3H, m) (*)20-26; R⁴=N(Me)Et(Method 2)

(2-Benzenesulfonyl-2,7,8,9-tetrahydro-6-oxo-2-aza-benzo[cd]azulen-8-yl)dimethylamine(20-1)

n-BuLi (1.56 mol/l hexane solution) 1.39 ml was added to a solution ofcompound (19-1) 432 mg in dry tetrahydrofuran 10 ml at −70° C. undernitrogen atmosphere. The solution was stirred at that temperature for 1h and at −30° C. for 1 h. Then, the temperature was again lowered to−70° C. and benezenesulofonyl chloride 396 mg was added dropwise. Thereaction temperature was allowed to raise gradually to the roomtemperature. The mixture was stirred at room temperature, poured to iceand an aqueous ammonium chloride solution and extracted with chloroform.The chloroform layer was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residueobtained was choromatographed on aluminum oxide 12 g inchloroform:hexane (8:1) to give the titled compound as crystals. Yield83%. The product was recrystallized from ethyl acetate isopropyl etherto give colorless crystals. m.p. 114-116° C.

¹H-NMR(CDCl₃): 2.36 (6H, s), 2.80-3.12 (3H, m), 4.13 (1H, dd, J=12.3,6.6 Hz), 4.42 (1H, dd, J=12.3, 0.6 Hz), 6.75 (1H, d, J=8.1 Hz),7.14-7.20 (1H, m), 7.34 (1H, s), 7.41-7.61 (4H, m), 7.86-7.89 (2H, m)

Example 14(1-Bromo-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine(21),(1,5-Dibromo-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethyl-amine(22) and(1,3-Dibromo-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethyl-amine(23)

N-Bromosuccinimide 214 mg was added to a warm solution of compound(19-1) 216 mg in carbon tetrachloride 33 ml and the mixture was heatedunder reflux for 2 h. After the reaction ceased, the insoluble materialswere removed by filtration and washed with chloroform. The filtrate wasconcentrated under reduced pressure. The residue obtained waschromatographed on silica gel in chloroform:methanol (30:1). The eluentwas chromatographed on thin silica gel plates in chloroform:methanol(30:1) to give the titled compound (21) 51 mg. Yield 17%. This wasrecrystallized from ethyl acetate-ether to give crystals, m.p. 170-172°C.

¹H-NMR(CDCl₃): 2.43 (6H, s), 2.88-3.08 (3H, m), 4.15 (1H, dd, J=12.3,6.0 Hz), 4.52 (1H, d, J=12.3 Hz), 6.62 (1H, dd, J=7.8, 0.9 Hz), 6.89(1H, dd, J=8.1, 0.9 Hz), 7.04 (1H, t, J=7.8 Hz), 8.07 (1H, br s)

1,5-Dibromo compound (22) 15 mg was isolated from another fraction.Yield 4% Purifying from ether gave crystals, m.p. 123-126° C.

¹H-NMR(CDCl₃): 2.44 (6H, s), 2.84-3.08 (3H, m), 4.21 (1H, dd, J=12.0,6.9 Hz), 4.66 (1H, d, J=12.0 Hz), 6.78 (1H, d, J=8.7 Hz), 7.25 (1H, d,J=8.7 Hz), 8.49 (1H, br s)

The mother liquor of the above mentioned 1,5-dibromo compound (22) wasconcentrated under reduced pressure and again chromatographed on thinsilica gel plates in chloroform:methanol (30:1) to give the 1,3-dibromocompound (23) 8 mg (yield 2%). This was treated with 1 eq. oxalic acidto give the salt, m.p. 147-152° C. (dec.).

¹H-NMR(CDCl₃): 2.42 (6H, s), 2.90-3.05 (3H, m), 4.09-4.16 (1H, m), 4.50(1H, d, J=12.0 Hz), 6.53 (1H, d, J=8.1 Hz), 7.15 (1H, d, J=8.1 Hz), 8.22(1H, br s)

Example 152-Chloro-N-(2,7,8,9-tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-yl)acetamide(24-1) (R═COCH₂Cl)

Compound (8-1) 535 mg was dissolved in dry tetrahydrofuran 15 ml.Triethylamine 345 mg and chloroacetyl chloride 0.25 ml were added to thesolution with cooling in ice. The mixture was stirred for 1 h and atroom temperature for 30 min. Ice-water was added to the mixture withcooling in ice. The mixture was extracted with ethyl acetate. Theextracts were washed with brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue obtained waschromatographed on silica gel 25 g in ethyl acetate:hexane (2:1) to givethe titled compound 706 mg (94%) as a colorless oil.

¹H-NMR(CDCl₃): 3.06-3.14 (1H, m), 3.36-3.43 (1H, m), 3.95-4.06 (2H, m),4.08-4.16 (1H, m), 4.27 (1H, d, J=11.4 Hz), 4.54-4.64 (2H, m), 6.70 (1H,dd, J=7.5, 1.2 Hz), 6.99 (1H, s), 7.03-7.13 (2H, m), 8.18 (1H, br s)

Following compounds were obtained, according to the similar treatment.

Compd No R m.p. ¹H-NMR (CDCl₃) 24-2 COOMe Colorless 3.02-3.07 (1H, m),3.33-3.39 (1H, oil m), 3.63 (3H, s), 4.23 (1H, d, J=9.3 Hz), 4.34-4.41(1H, m), 4.53-4.60 (1H, m), 5.25 (1H, br d), 6.67 (1H, d, J=7.8 Hz),6.97 (1H, s), 7.00-7.11 (2H, m), 8.14 (1H, br s) 24-3 Ms Colorless 3.02(3H, s), 3.07-3.14 (1H, m), oil 3.35-3.42 (1H, m), 4.19-4.27 (2H, m),4.54-4.61 (1H, m), 4.84 (1H, d, J=8.7 Hz), 6.68 (1H, d, J=7.5 Hz),7.00-7.12 (3H, m), 8.22 (1H, br s) 24-4 SO₂NHMe Yellow 2.70 (3H, d,J=5.4 Hz), 3.04-3.11 oil (1H, m), 3.35-3.42 (1H, m), 4.03- 4.28 (3H, m),4.53-4.60 (1H, m), 4.81 (1H, d, J=8.4 Hz), 6.67 (1H, dd, J=7.2, 1.2 Hz),6.98-7.11 (3H, m), 8.24 (1H, br s) 24-5 COMe 174-176 1.92 (3H, s),2.99-3.06 (1H, m), 3.35-3.41 (1H, m), 4.21-4.25 (1H, m), 4.53-4.68 (2H,m), 6.03 (1H, br s), 6.69 (1H, d, J=7.2 Hz), 6.98 (1H, s), 7.03-7.13(2H, m), 8.21 (1H, br s)

Example 162-Cyclohexylamino-N-(2,7,8,9-tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-yl)acetamide(25-1)

A solution of compound (24-1) 160 mg and cyclohexylamine 360 mg inbenzene 4 ml and methanol 4 ml was heated at 60° C. for 21 h andconcentrated under reduced pressure. Water was added to the residueobtained. The mixture was extracted with chloroform. The extracts werewashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschromatographed on silica gel in ethyl acetate:methanol (30:1) to givethe titled compound 161 mg as crystals. Yield 81%. The crude crystallinematerials were recrystallized from methanol-ethyl acetate to givecolorless crystals, m.p. 184-186° C.

¹H-NMR(CDCl₃): 0.43-1.04 (4H, m), 1.22-1.57 (6H, m), 1.98-2.07 (1H, m),3.02-3.46 (4H, m), 4.24-4.29 (1H, m), 4.54-4.59 (2H, m), 6.69 (1H, dd,J=7.5, 0.9 Hz), 6.96-7.11 (3H, m), 7.96 (1H, br s), 8.13 (1H, br s)

Following compounds were obtained, according to the similar treatment.

Compd No R m.p. ¹H-NMR (CDCl₃) 25-2 NMe₂ 161- 2.06 (6H, s), 2.84-2.96(2H, m), 3.06-3.13 162.5 (1H, m), 3.31-3.39 (1H, m), 4.26 (1H, d, J=11.4Hz), 4.52-4.62 (2H, m), 6.68 (1H, dd, J=7.5, 0.9 Hz), 6.97-7.11 (3H, m),7.53 (1H, br s), 8.21 (1H, br s)

Scheme of Reactions, Examples 17-25

Example 17((R)-1-Phenylethyl)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine(26)

Sodium triacetoxyborohydride 318 mg and acetic acid 57 μl were added toa solution of compound (18-1) 187.6 mg and (R)-(+)-α-methylbenzylamine13.7 mg in dry tetrahydrofuran 8 ml at room temperature and the mixturewas stirred for 18 h. Water was added. The reaction mixture was madealkaline with an aqueous saturated sodium hydrogencarabonate solutionand extracted with ether. The extracts were washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue obtained was chromatographed on aluminum oxide 40g in ethyl acetate:hexane (1:2) to give the titled compound 250 mg as acolorless oil. Yield 86%. The ¹H-NMR shows the titled compound is amixture of their diastereomers.

¹H-NMR(CDCl₃): 1.33 (total 6H, d, J=6.6 Hz), 2.98-3.22 (total 6H, m),4.04-4.41 (total 6H, m), 6.61-6.65 (total 2H, m), 6.91-7.41 (total 16H,m), 8.07 (total 2H, br s).

Example 182,2,2-Trifluoro-N-((R)-1-phenylethyl)-N-(S)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylacetamide(27) and2,2,2-Trifluoro-N-((R)-1-phenylethyl)-N-(R)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylacetamide(28)

Compound (26) 2.548 g was dissolved in dry tetrahydrofuran 8 ml. Asolution of triethylamine 1.34 ml and trifluoroacetic anhydride 2.014 gin dry tetrahydrofuran 1 ml was added to the solution with cooling inice. The mixture was stirred for 1 h. Furthermore, triethylamine 177 mg,trifluoroacetic anhydride 366 mg were added and the mixture was stirredfor 1 h with cooling in ice. The solvents were removed by distillationunder reduced pressure. Water was added to the residue. The mixture wasextracted with ether. The extracts were washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue obtained was chromatographed on silica gel in ethylacetate:hexane (1:5) repeatedly to give the titled compound (27) as acolorless oil, 990 mg (yield 29%) and the titled compound (28) as acolorless oil 1.672 g (yield 49%).

Compound (27)

¹H-NMR(CDCl₃): 1.82 (3H, d, J=6.9 Hz), 2.07-2.19 (1H, m), 3.54-3.66 (2H,m), 4.43 (1H, dd, J=12.9, 2.4 Hz), 4.81 (1H, dd, J=12.9, 6.0 Hz), 5.40(1H, q, J=6.9 Hz), 6.61 (1H, dd, J=7.5, 0.9 Hz), 6.64 (1H, m), 6.94 (1H,dd, J=7.5, 0.9 Hz), 7.04 (1H, t, J=7.5 Hz), 7.27-7.40 (5H, m), 7.96 (1H,br s).

Compound (28)

¹H-NMR(CDCl₃): 1.72 (3H, d, J=6.9 Hz), 3.00-3.08 (1H, m), 3.55-3.63 (1H,m), 3.85-3.96 (1H, m), 4.10 (1H, dd, J=12.6, 2.4 Hz), 4.63 (1H, dd,J=12.6, 6.3Hz), 5.39 (1H, q, J=6.9 Hz), 6.43 (1H, dd, J=7.5, 1.2 Hz),6.91-7.01 (3H, m), 7.34-7.44 (5H, m), 8.08 (1H, br s).

Example 19((R)-1-Phenylethyl)-(S)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine(29)

Compound (27) 934 mg was dissolved in ethanol 19 ml and sodiumborohydride 364 mg was added to the solution at room temperature. Themixture was stirred for 17 h. Water was added with cooling in ice. Themixture was extracted with ethyl acetate. The extracts were washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue obtained was chromatographed on silica gelin ethyl acetate:hexane (1:1) to give the titled compound (29) 695 mg.Yield 99.9%. Furthermore, the titled compound (29) was treated with asolution of hydrogen chloride in methanol to give the HCl salt, whichwas recrystallized from methanol-isopropanol to give colorless crystals,m.p. 233-240° C. (dec.). The absolute configuration was determined by anX-ray crystal structure analysis on a single crystal.

¹H-NMR(CDCl₃): 1.33 (3H, d, J=6.3 Hz), 3.00-3.22 (3H, m), 4.03 (1H, q,J=6.3 Hz), 4.21 (1H, d, J=11.7 Hz), 4.29-4.36 (1H, m), 6.63 (1H, dd,J=7.8, 0.9 Hz), 6.95-6.99 (2H, m), 7.06 (1H, t, J=7.8 Hz), 7.20-7.42(5H, m), 8.07 (1H, br s).

According to the similar manner,((R)-1-Phenylethyl)-(R)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine(30) was obtained.

¹H-NMR(CDCl₃): 1.33 (3H, d, J=6.6 Hz), 2.80-3.15 (3H, m), 4.11 (1H, q,J=6.3 Hz), 4.26 (1H, d, J=12.0 Hz), 4.37 (1H, dd, J=12.0, 6.3 Hz), 6.64(1H, dd, J=7.8, 0.9 Hz), 6.91-6.93 (1H, m), 6.96 (1H, dd, J=7.8, 0.9Hz), 7.06 (1H, t, J=7.8 Hz), 7.20-7.41 (5H, m), 8.06 (1H, br s).

Example 20 (S)-2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine(31)

Compound (29) 609 mg was dissolved in tetrahydrofuran 20 ml. 20%Palladium(II)hydroxide 200 mg was added. A mixture was stirred in ahydrogen atomosphere for 22 h. The catalyst was filtered off and thefiltrate was concentrated under reduced pressure. The residue obtainedwas chromatographed on aluminum oxide in chloroform to give the titledcompound (31) as pale brown crystals, 337 mg. Yield 86%. Furthermore,this was recrystallized from methanol-isopropanol to give the titledcompound (31) as pale brown crystals, m.p. 202-203° C.

[α]_(D)+38.7±1.6° (C=0.509, methanol, 25° C.)

According to the similar manner,(R)-2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine (32) wasobtained.

m.p. 202-203° C. [α]_(D)−38.8±1.6° (C=0.508, methanol, 25° C.)

Example 21 2,9-Dihydro-6-oxa-2-azabenzo[cd]azulen-8-one ethylene ketal(33)

Ethylene glycol 2.56 g and pyridinium p-toluenesulfonate 250 mg wereadded to a solution of compound (18-1) 1.877 g in benzene 50 ml. Themixture was heated under reflux for 14 h by use of a Dean-Starkapparatus. The reaction mixture separated into two layers. The upperlayer was separated by decantation. Water and dioxane were added to theremained black oily part. The insoluble materials were removed byfiltration and the filtrate was extracted with toluene. The extractswere washed with brine, treated with char coal, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to give browncrystals. The above obtaied upper layer was washed with water, anaqueous saturated sodium hydrogen carbonate solution and brinesuccessively, treated with char-coal and dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give colorlesscrystals. The combined crystals were recrystallized from tetrahydrofuranto give the titled compound (33) as colorless crystals, m.p. 200-202°C., 925 mg. Yield 40%.

¹H-NMR(DMSO-d₆): 3.16 (2H, s), 3.97 (4H, s), 4.13 (2H, s), 6.41 (1H, dd,J=6.6, 1.8 Hz), 6.88-6.96 (2H, m), 7.07 (1H, m), 10.94 (1H, br s).

Example 222-Benzenesulfonyl-2,9-dihydro-6-oxa-2-azabenzo[cd]azulen-8-one ethyleneketal (34)

60% Sodium hydride 33 mg was added to a solution of compound (33) in drydimethylformamide 2 ml with cooling in ice and the mixture was stirredfor 10 min. Then, benzenesulfonyl chloride 152 mg was added. The mixturewas heated at 60° C. for 14 h. Ice-water was added to the reactionmixtures, which was extracted with ethyl acetate. The extracts werewashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschoromatographed on aluminum oxide in chloroform:hexane (1:1) to givethe titled compound (34) as a pale yellow oil, 187 mg. Yield 69%.

¹H-NMR(CDCl₃): 3.22 (2H, s), 4.07 (4H, s), 4.16 (2H, s), 6.80 (1H, dd,J=8.1, 0.9 Hz), 7.18 (1H, t, J=8.1 Hz), 7.33 (1H, m), 7.42-7.58 (3H, m),7.62 (1H, dd, J=8.4, 0.9 Hz), 7.88-7.92 (2H, m).

Example 232-Benzenesulfonyl-2,9-dihydro-6-oxa-2-azabenzo[cd]azulen-8-one (35)

Trifluoroacetic acid 1 ml and water 0.1 ml were added to compound (34)48.4 mg. The mixture was heated at 80° C. for 15 min and concentratedunder reduced pressure. Ice-water was added to the residue, which wasmade alkaline with an aqueous saturated sodium hydrogen carbonatesolution and extracted with ethyl acetate. The extracts were washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue obtained was chromatographed on silica gelin ethyl acetate:hexane (1:2) to give the titled compound (35) as acolorless oil, 33.2 mg. Yield 78%.

¹H-NMR(CDCl₃): 4.03 (2H, d, J=1.2 Hz), 4.62 (2H, s), 6.90 (1H, dd,J=7.8, 0.6 Hz), 7.25 (1H, t, J=7.8 Hz), 7.30 (1H, m), 7.44-7.61 (3H, m),7.73 (1H, dd, J=7.8, 0.6 Hz), 7.88-7.93 (2H, m).

Example 242-Benzenesulfonyl-8-pyrrolidin-1-yl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulene(36-1) (R⁴=pyrrolidinyl)

A solution of pyrrolidine 35.4 mg in dry tetrahydrofuran 0.5 ml, sodiumtriacetoxyborohydride 133.7 mg and acetic acid 26 μl were added to asolution of compound (35) 135.9 mg in dry tetrahydrofuran 3.5 ml at roomtemperature and the mixture was stirred for 24 h. Water was added to thereaction mixture, which was made alkaline with an aqueous saturatedsodium hydrogencarbonate solution and extracted with ethyl acetate. Theextracts were washed with brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue obtained waschromatographed on aluminum oxide 20 g in chloroform to give the titledcompound (36-1) as a brown oil, 97.7 mg. Yield 62%. This was treatedwith 1 eq. oxalic acid to give the salt which was recrystallized fromether-methanol to give colorless crystals, m.p. 170-173° C.(dec.).

¹H-NMR(CDCl₃): 1.76-1.84 (4H, m), 2.60-3.26 (7H, m), 4.12 (1H, dd,J=12.9, 6.3 Hz), 4.47 (1H, d, J=12.9 Hz), 6.73 (1H, dd, J=8.1, 0.9 Hz),7.17 (1H, t, J=8.1 Hz), 7.33 (1H, s), 7.41-7.61 (4H, m), 7.86-7.90 (2H,m).

Following compounds were obtained, according to the similar treatment.

Compd m.p. No R⁴ (° C.) ¹H-NMR (CDCl₃) 36-2 NHMe 208-213 2.52 (3H, s),2.91-3.15 (3H, m), (dec.) 4.22-4.27 (2H, m), 6.76 (1H, dd, J=8.1,oxalate 0.9 Hz), 7.18 (1H, t, J=8.1 Hz), 7.32-7.34 (1H, m), 7.41-7.58(3H, m), 7.61 (1H, dd, J=8.1, 0.9 Hz), 7.86-7.90 (2H, m) 36-3 NEt₂106-108 1.07 (6H, t, J=6.9 Hz), 2.50-3.30 (7H, m), 3.98-4.05 (1H, m),4.52 (1H, d, J=11.7 Hz), 6.74 (1H, dd, J=7.8, 0.9 Hz), 7.17 (1H, t,J=7.8 Hz), 7.33 (1H, s), 7.42-7.62 (4H, m), 7.86-7.90 (2H, m) 36-4 NHBn208-209 2.94-3.11 (2H, m), 3.20-3.27 (1H, m), (dec.) 3.86 (1H, d, J=13.2Hz), 3.95 (1H, d, oxalate J=13.2 Hz), 4.27 (2H, d, J=3.9 Hz), 6.77 (1H,d, J=7.8 Hz), 7.15-7.62 (11H, m), 7.86-7.90 (2H, m)

Example 25 2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ol(37)

Compound (18-1) 374.4 mg was suspended in methanol 5 ml and sodiumborohydride 75.7 mg was added to the suspension with cooling in ice. Themixture was stirred for 1 h. Water was added with cooling in ice. Themixture was extracted with ethyl acetate. The extracts were washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue obtained was recrystallized fromacetone-isopropanol to give the titled compound (37) as colorlesscrystals m.p. 169-170° C., 356.5 mg. Yield 94%.

¹H-NMR(CD₃OD): 2.83-2.93 (1H, m), 3.29-3.38 (1H, m), 4.03-4.17 (2H, m),4.32 (1H, dd, J=5.4, 2.1 Hz), 6.42-6.48 (1H, m), 6.88-6.95 (1H, m), 6.99(1H, br s).

Scheme of Reactions, Examples 26-34

Example 26Dimethyl-(5-phenyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)amine(38)

Phenylboronic acid 190.1 mg, palladium acetate 13.0 mg,tris(2-methylphenyl)phosphine 30.9 mg and potassium carbonate 691.0 mgwere added to a solution of compound (19-16) 296 mg in drydimethylformamide 6 ml under nitrogen atmosphere. The mixture was heatedat 120° C. for 2 h. After cooling, water was added. The mixture wasextracted with ethyl acetate. The extracts were washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue obtained was chromatographed on aluminum oxide inethyl acetate:toluene (1:2) to give the titled compound (38) ascolorless crystals, 33.0 mg. Yield 11%. Furthermore, the titled compoundwas recrystallized from acetone-isopropyl ether to give colorlesscrystals, m.p. 168-170° C.

¹H-NMR(CDCl₃): 2.42 (6H, s), 2.96-3.28 (3H, m), 4.17 (1H, dd, J=12.3,6.3 Hz), 4.53 (1H, d, J=12.3 Hz), 7.02 (1H, s), 7.03 (1H, d, J=8.4 Hz),7.15 (1H, d, J=8.4 Hz), 7.27-7.60 (5H, m).

Example 27(E)-3-(8-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-5-yl)acrylicacid methyl ester (39)

Methyl acrylate 140 μl, triethylamine 217 μl andbis(triphenylphosphine)palladium dichloride 0.2 mg were added to asolution of compound (19-16) 306 mg in dry dimethylformamide 5 ml undernitrogen atmosphere. The mixture was heated at 100° C. for 19 h. Waterwas added with cooling in ice. The mixture was extracted with ethylacetate. The extracts were washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residueobtained was chromatographed on aluminum oxide in ethyl acetate:hexane(1:1) to give the titled compound as yellow crystals 146.5 mg. Yield47%. The titled compound was recrystallized from acetone-isopropyl etherto give pale yellow crystals, m.p. 168-170° C.

¹H-NMR(CDCl₃): 2.43 (6H, s), 2.90-3.22 (3H, m), 3.80 (3H, s), 4.24 (1H,dd, J=12.0, 6.6 Hz), 4.63 (1H, dd, J=12.6, 0.9 Hz), 6.39 (1H, d, J=16.2Hz), 6.94 (1H, d, J=8.7 Hz), 6.97 (1H, m), 7.34 (1H, d, J=8.7 Hz), 8.22(1H, br s), 8.25 (1H, d, J=16.2 Hz).

Example 28Dimethyl-(5-vinyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)amine(40)

Tri-n-butylvinyltin 952.0 mg, tetrakistriphenylphosphinepalladium 116.1mg and lithium chloride 254.0 mg were added to a solution of compound(19-16) 592.2 mg in dry dimethylformamide 30 ml under a nitrogenatmosphere. The mixture was heated at 120° C. for 4 h and diluted withethyl acetate, after cooling. The insoluble materials were removed byfiltration through cerite. The filtrate was washed with an aqueoussaturated sodium hydrogencarbonate solution and brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue obtained was chromatographed on aluminum oxide in ethylacetate:toluene (1:2) to give a colorless oil 602.2 mg. This waschromatographed on silica gel in chloroform:methanol:aq. ammonia(46:10:1) to give a yellow oil 500 mg, which was crystallized fromhexane giving the titled compound as colorless crystals, 324 mg. Yield67%. Furthermore, the titled compound was recrystallized fromether-petroleumether to give colorless crystals, m.p.119-120° C.

¹H-NMR(CDCl₃): 2.43 (6H, s), 2.93-3.23 (3H, m), 4.12-4.19 (1H, m), 4.61(1H, dd, J=12.6, 1.5 Hz), 5.13 (1H, dd, J=11.4, 1.5 Hz), 5.62 (1H, dd,J=18.0, 1.5 Hz), 6.91-6.96 (2H, m), 7.22 (1H, dd, J=18.0, 11.4 Hz), 7.34(1H, d, J=8.4 Hz), 8.08 (1H, br s).

Example 29(5-Ethyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine(41)

Compound (40) 242 mg was dissolved in methanol 4 ml and 5% palladium/C60 mg was added. A mixture was stirred in hydrogen atmosphere at roomtemperature for 3 h. The catalyst was filtered off and the filtrate wasconcentrated under reduced pressure. The residue obtained waschromatographed on aluminum oxide in ethyl acetate:hexane (1:2) to givethe titled compound as colorless crystals 241.6 mg. Yield 99%. This wasrecrystallized from acetone-hexane to give the titled compound ascolorless crystals, m.p. 91-92° C.

¹H-NMR(CDCl₃): 1.21 (3H, t, J=7.5 Hz), 2.44 (6H, s), 2.65-2.78 (2H, m),2.94-3.23 (3H, m), 4.12-4.18 (1H, m), 4.54-4.59 (1H, m), 6.90 (1H, d,J=8.4 Hz), 6.94-6.96 (1H, m), 6.97 (1H, d, J=8.4 Hz), 7.96 (1H, br s).

Example 30(5-Bromo-2-triisopropylsilanyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine(42)

Compound (19-16) 2.00 g was added to a suspension of 60% sodium hydride300.8 mg in tetrahydrofuran 30 ml with cooling in ice. The mixture wasstirred for 1 h. Then, triisopropylsilyl chloride (TIPSCl) 1.6 ml wasadded with cooling in ice. The mixture was stirred for 4 h with coolingin ice. Water was added to reaction mixture with cooling in ice. Themixture was extracted with ethyl acetate. The extracts were washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue obtained was chromatographed on aluminumoxide in ethyl acetate:hexane (1:4) to give a pale brown oil 2.67 g.This was recrystallized from isopropyl ether to give colorless crystals,m.p. 119-121° C. 1.85 g. Yield 60%.

¹H-NMR(CDCl₃): 1.13 (18H, dd, J=7.5, 0.9 Hz), 1.58-1.72 (3H, m), 2.45(6H, s), 3.03-3.26 (3H, m), 4.18-4.24 (1H, m), 4.66 (1H, dd, J=12.3, 1.5Hz), 6.96 (1H, d, J=8.7 Hz), 7.00 (1H, s), 7.20 (1H, d, J=8.7 Hz).

Example 31(5-Fluoro-2-triisopropylsilanyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine(43)

A solution of compound (42) 451 mg in dry tetrahydrofuran 5 ml wascooled at −70° C. n-BuLi (1.56 mol/l hexane solution) 1.3 ml was addeddropwise to the mixture, which was stirred for 1 h. Then,N-fluorobenzenesulfonimide 694 mg was added and the mixture was stirredfor 3.5 h. The reaction mixtures was diluted with an aqueous ammoniumchloride solution, extracted with ethyl acetate. The extracts werewashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschromatographed on aluminum oxide in ethyl acetate:hexane (1:5) to givea yellow oil. This was chromatographed on thin aluminum oxide plates(Merck precoated TLC plate alumina 60F254 in ethyl acetate:hexane (1:5))to give the titled compound as a pale yellow oil, 100 mg.

¹H-NMR(CDCl₃): 1.28 (18H, dd, J=7.5, 0.9 Hz), 1.58-1.70 (3H, m), 2.45(6H, s), 2.95-3.28 (3H, m), 4.20-4.26 (1H, m), 4.62 (1H, dd, J=11.7, 1.2Hz), 6.86-6.97 (2H, m), 7.03 (1H, s).

Example 32Dimethyl-(5-methylsulfanyl-2-triisopropylsilanyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulen-8-yl)amine(44)

A solution of compound (42) 451 mg in dry tetrahydrofuran 5 ml wascooled at −70° C. n-BuLi (1.56 mol/l hexane solution) 1.3 ml was addeddropwise to the solution and the mixture was stirred for 1 h. Then,dimethyldisulfide 185 μl was added and the mixture was stirred for 2 h.The reaction mixtures was diluted with an aqueous ammonium chloridesolution and extracted with ethyl acetate. The extracts were washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue obtained was chromatographed on aluminumoxide in ethyl acetate:hexane (1:5) to give the titled compound ascolorless crystals, 289.8 mg. Yield 69%. This was recrystallized fromhexane to give the titled compound as colorless crystals, m.p. 77-79° C.

¹H-NMR(CDCl₃): 1.13 (18H, d, J=7.5 Hz), 1.58-1.74 (3H, m), 2.45 (total9H, each s), 2.97-3.30 (3H, m), 4.22 (1H, d, J=12.0, 6.3 Hz), 4.68 (1H,dd, J 12.0, 1.2 Hz), 6.99 (1H, s), 7.04 (1H, d, J=8.4 Hz), 7.10 (1H, d,J=8.7 Hz).

Example 338-Dimethylamino-2-triisopropylsilanyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulene-5-carbaldehyde(45)

A solution of compound (42) 750 mg in dry tetrahydrofuran 7 ml wascooled at −70° C. and n-BuLi (1.56 mol/l hexane solution) 2.2 ml wasadded dropwise to the solution. The mixture was stirred for 1 h.Dimethylformamide 257 μl was added and the mixture was stirred for 2 h.The reaction mixtures was diluted with an aqueous ammonium chloridesolution and extracted with ethyl acetate. The extracts were washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue obtained was chromatographed on aluminumoxide in ethyl acetate:hexane (1:4) to give the titled compound asyellow oil, 556 mg. This was recrystallized from hexane to give thetitled compound as colorless crystals, m.p. 104-106° C., 395 mg. Yield59%

¹H-NMR(CDCl₃): 1.14 (18H, d, J=7.5 Hz), 1.55-1.72 (3H, m), 2.45 (6H, s),2.97-3.30 (3H, m), 4.29 (1H, dd, J=12.6, 6.3 Hz), 4.65 (1H, d, J=12.6Hz), 7.04 (1H, s), 7.07 (1H, d, J=9.0 Hz), 7.60 (1H, d, J=8.7 Hz), 10.50(1H, s).

Example 348-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulene-5-carbaldehyde(46-1) (R₁₁═CHO)

Tetra-n-butylammoniumfluoride (1 mol/l tetrahydrofuran solution) 2.2 mlwas added to compound (45) 496 mg in tetrahydrofuran 10 ml with coolingin ice. The mixture was stirred for 3 h, diluted with water and ethylacetate and, extracted with ethyl acetate. The extracts were washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue obtained was chromatographed on aluminumoxide in ethyl acetate:hexane (2:1) to give colorless crystals, 273.2mg. This was recrystallized from acetone-isopropyl ether to give thetitled compound as colorless crystals, m.p.175-176° C., 2654 mg. Yield88%.

¹H-NMR(DMSO-d₆): 2.29 (6H, s), 2.78-3.13 (3H, m), 4.31 (1H, dd, J=12.3,6.6 Hz), 4.58 (1H, d, J=12.3 Hz), 6.99 (1H, dd, J=8.4, 0.9 Hz), 7.23(1H, s), 7.40 (1H, d, J=8.4 Hz), 10.36 (1H, d, J=0.9 Hz), 11.48 (1H, brs).

Following compounds were obtained, according to the similar treatment.

Compd m.p. No R¹¹ (° C.) ¹H-NMR (CDCl₃) 46-2 F 148-150 2.44 (6H, s),2.93-3.25 (3H, m), 4.24 (1H, dd, J=12.3, 6.6 Hz), 4.63 (1H, dd, J=12.3,1.2 Hz), 6.83 (1H, dd, J=8.7, 3.6 Hz), 6.97 (1H, dd, J=11.4, 8.7 Hz),7.01 (1H, m), 8.04 (1H, br s) 46-3 SMe 112-113 2.44 (3H, s), 2.44 (6H,s), 2.97-3.24 (3H, m), 4.24 (1H, dd, J=12.3, 6.3 Hz), 4.69 (1H, dd,J=12.3, 2.1 Hz), 6.94 (1H, d, J=8.4 Hz), 6.97-6.99 (1H, m), 7.19 (1H, d,J=8.7 Hz), 8.09 (1H, br s)

Scheme of Reactions, Examples 35-37

Example 358-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulene-5-carbaldehydeOxime (47)

Hydroxylamine hydrogenchloride 83.4 mg and sodium acetate 98.4 mg wereadded to a suspension of compound (46-1) 244 mg in 95% ethanol 10 ml.The mixture was stirred at room temperature for 2 h and concentratedunder reduced pressure. Water was added to the residue, which was madealkaline with an aqueous saturated sodium hydrogencarbonate solution.Colorless precipitates appeared and were collected by filtration, washedwith methanol-ethyl acetate to give the titled compound as colorlesscrystals, m.p. 230-235° C.(dec.), 228 mg. Yield 88%.

¹H-NMR(DMSO-d₆): 2.28 (6H, s), 2.73-3.12 (3H, m), 4.15 (1H, dd, J=12.0,6.6 Hz), 4.49 (1H, d, J=12.3 Hz), 6.93 (1H, d, J=7.8 Hz), 7.13 (1H, brd, J=2.7 Hz), 7.38 (1H, d, J=8.7 Hz), 8.39 (1H, s), 10.66 (1H, s), 11.12(1H, br s).

Example 368-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulene-5-carbonitrile(48)

Triethylamine 33 μl and trichloroacetyl chloride 13 μl were added to asolution of compound (47) 28.9 mg in dichloromethane 2 ml with coolingice and the mixture was stirred with cooling in ice and at roomtemperature for 18 h. A saturated sodium hydrogencarbonate solution wasadded thereto for alkalinization. The mixture was extracted withchloroform. The extracts were washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residueobtained was chromatographed on aluminum oxide in chloroform:methanol(97:3) to give the titled compound 26.3 mg as colorless crystals. Yield98%. Furthermore, the titled compound was recrystallized frommethanol-isopropyl ether to give colorless crystals, m.p. 205-207° C.

¹H-NMR(CD₃OD): 2.41 (6H, s), 2.89-3.23 (3H, m), 4.39 (1H, dd, J=12.6,6.9 Hz), 4.64 (1H, d, J=12.6 Hz), 7.03 (1H, d, J=8.7 Hz), 7.17 (1H, d,J=8.7 Hz), 7.18 (1H, m).

Example 37 8-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulene-5-carboxylic acid amide (49)

Polyphophoric acid 420 mg was added to compound (48) 31.6 mg under anargon atmosphere and the mixture was heated at 90° C. for 6 h. Ice-waterwas added to the reaction mixture, which was made alkaline with anaqueous 5 N-sodium hydroxide solution and extracted with chloroform. Theextracts were washed with brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue obtained waschromatographed on aluminum oxide in chloroform:methanol (97:3) to givethe titled compound as colorless crystals, 20.9 mg. Yield 62%.Furthermore, the titled compound was recrystallized fromacetone-isopropyl ether to give colorless crystals, m.p. 182-183° C.

¹H-NMR(DMSO-d₆): 2.29 (6H, s), 2.76-3.13 (3H, m), 4.24 (1H, dd, J=12.0,6.0 Hz), 4.64 (1H, d, J=12.3 Hz), 6.97 (1H, d, J=8.7 Hz), 7.18 (1H, d,J=2.1 Hz), 7.22 (1H, br s), 7.66 (1H, d, J=8.7 Hz), 7.68(1H, br s),11.20 (1H, br s)

Scheme of Reactions, Examples 38-40

Example 38N-Cyclopropyl-2,2,2-trifluoromethyl-N-(2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)acetamide(50)

Compound (19-19) 355 mg was dissolved in dry tetrahydrofuran 11 ml. Asolution of triethylamine 178 mg and trifluoroacetic anhydride 344 mg indry tetrahydrofuran 0.5 ml was added to the solution with cooling inice. The mixture was stirred with cooling in ice for 2 h. Triethylamine78 mg and trifluoroacetic anhydride 156 mg in dry tetrahydrofuran 0.2 mlwere again added. The mixture was stirred with cooling in ice for 2 hand concentrated under reduced pressure. Water was added to the residue,which was extracted with ether. The extracts were washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue obtained was chromatographed on aluminum oxide 15g in chloroform:hexane (4:1) to give the titled compound as pale yellowcrystals, 415 mg (yield 82%), m.p. 49-53° C.

¹H-NMR(CDCl₃): 0.94-1.06 (4H, m), 3.04-3.14 (2H, m), 3.64-3.74 (1H, m),4.10-4.15 (1H, m), 4.46 (1H, dd, J=12.6, 1.8 Hz), 4.70 (1H, dd, J=12.6,6.6 Hz), 6.64 (1H, dd, J=7.5, 1.2 Hz), 6.97 (1H, s), 7.00 (1H, dd,J=8.1, 1.2 Hz), 7.08 (1H, d, J=8.1 Hz), 8.17 (1H, br s)

Example 39N-(2-Benzenesulfonyl-2,7,8,9-tetrahydro-6-oxo-2-aza-benzo[cd]azulen-8-yl)-N-cyclopropyl-2,2,2,-trifluoroacetamide(51)

60% Sodium hydride 56 mg was added to a solution of compound (50) 324 mgin dimethylformamide 12 ml with cooling in ice and the mixture wasstirred at room for 1 h. Benzenesulfonyl chloride 238 mg was addeddropwise with cooling in ice and then, the mixture was stirred at 40° C.for 21 h. Ice-water and then an aqueous sodium hydrogencarbonatesolution were added to the reaction mixture, which was extracted withethyl acetate. The extracts were washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residueobtained was chromatographed on aluminum oxide in chloroform:hexane(1:2) to give the titled compound as a colorless oil, 130 mg (yield28%).

¹H-NMR(CDCl₃): 0.88-1.05 (4H, m), 3.03-3.09 (2H, m), 3.58-3.68 (1H, m),3.99-4.06 (1H, m), 4.40 (1H, dd, J=12.9, 1.5 Hz), 4.59 (1H, dd, J=12.9,6.3 Hz), 6.77 (1H, dd, J=7.8, 0.6 Hz), 7.20 (1H, t, J=8.1 Hz), 7.34 (1H,s), 7.44-7.66 (4H, m), 7.86-7.90 (2H, m)

Example 40(2-Benzenesulfonyl-2,7,8,9-tetrahydro-6-oxo-2-aza-benzo[cd]azulen-8-yl)cyclopropylamine(52)

Compound (51) 129 mg was dissolved in ethanol 3 ml. Sodiumhydrogenborohydride 42 mg was added to the solution at room temperatureand the mixture was stirred for 23 h. Water was added with cooling inice to the reaction mixture, which was extracted with chloroform. Theextracts were washed with brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue obtained waschromatographed on aluminum oxide in chloroform:hexane (1:1) to give thetitled compound as a colorless oil, 98 mg. Yield 96%. The titledcompound was treated with 1 eq. of oxalic acid to give the salt, whichwas recrystallized from isopropanol-ether to give colorless crystals,m.p. 119-122° C. (dec.).

¹H-NMR(CDCl₃): 0.30-0.49 (4H, m), 2.21-2.27 (1H, m), 2.94-3.12 (2H, m),3.31-3.37 (1H, m), 4.29-4.31 (2H, m), 6.77 (1H, d, J=7.8 Hz), 7.19 (1H,t, J=8.1 Hz), 7.33 (1H, s), 7.42-7.63 (4H, m), 7.86-7.90 (2H, m)

Scheme of Reactions, Examples 41-44

Example 41(2-Benzenesulfonyl-1-iodo-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine(53)

LDA was prepared by addition of n-BuLi (1.56 mol/l hexane solution) 1.08ml to a solution of diisopropylamine 255 μl in dry tetrahydrofuran 3 mlat −70° C. Then, a solution of compound (20-1) 500 mg in drytetrahydrofuran 2 ml was added at that temperature to the mixture, whichwas stirred for 2 h. Then, a solution of iodine 426 mg in drytetrahydrofuran 2 ml was added and the mixture was stirred for 2 h. Icewas added to the reaction mixtures, which was extracted with chloroform.The extracts were washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue obtainedwas chromatographed on aluminum oxide in ethyl acetate:hexane (1:5) togive the titled compound as colorless crystals 514 mg. Yield 76%. Thiswas recrystallized from from acetone-isopropyl ether to give colorlesscrystals, m.p. 136-137° C.

¹H-NMR(CDCl₃): 2.36 (6H, s), 2.87-2.97 (3H, m), 4.08-4.14 (1H, m), 4.41(1H, d, J=12.6 Hz), 6.75 (1H, d, J=7.5 Hz), 7.40-7.45 (2H, m), 7.53-7.58(1H, m), 7.86-7.90 (2H, m), 7.96 (1H, d, J=7.8 Hz).

Example 42(2-Benzenesulfonyl-1-vinyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine(54)

Tri-n-butyl(vinyl)tin 484.4 mg, tetrakis(triphenylphosphine)palladium690 mg and lithium chloride 127.7 mg were added to a solution ofcompound (53) 491 mg in dry dimethylformamide 10 ml under nitrogenatmosphere. The mixture was heated at 100° C. for 3 h, diluted withethyl acetate after cooling and filtered through cerite to remove theinsoluble materials. The filtrate was washed with an aqueous saturatedsodium hydrogencarbonate solution and brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residueobtained was pulverized in hexane, collected by filtration andchromatographed on aluminum oxide in chloroform:hexane (1:1) to give thetitled compound as colorless crystals 602.2 mg. Yield 79%. Furthermore,the titled compound was recrystallized from acetone-isopropyl ether togive colorless crystals, m.p. 133-134° C.

¹H-NMR(CDCl₃): 2.53 (6H, s), 2.78-3.10 (3H, m), 4.11 (1H, dd, J=12.6,6.6 Hz), 4.41 (1H, d, J=12.6 Hz), 5.36 (1H, dd, J=17.7, 1.5 Hz), 5.69(1H, dd, J=11.4, 1.5 Hz), 6.77 (1H, dd, J=8.1, 0.9 Hz), 7.18 (1H, dd,J=18.0, 11.4 Hz), 7.19 (1H, t, J=8.1 Hz), 7.34-7.53 (3H, m), 7.73-7.76(2H, m), 7.87 (1H, dd, J=8.4, 0.9 Hz).

Example 43(2-Benzenesulfonyl-1-ethyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine(55)

Compound (54) 200.1 mg was dissolved in a mixture of methanol 8 ml andtetrahydrofuran 4 ml. 10% Pd/C 49.8 mg was added. The mixture wasstirred under hydrogen atmosphere for 18 h at room temperature. Thecatalyst was filtered off and the filtrate was concentrated underreduced pressure. The residue obtained was chromatographed on aluminumoxide in chloroform:hexane (1:1) to give the titled compound as acolorless oil 198 mg. Yield 98%. This was treated with 1 eq. of oxalicacid to give the salt, which was recrystallized from ether-methanol togive colorless crystals, m.p. 193-194° C.(dec.).

¹H-NMR(CDCl₃): 1.28 (3H, t, J=7.5 Hz), 2.41 (6H, s), 2.89-3.07 (5H, m),4.07-4.13 (1H, m), 4.43 (1H, d, J=12.6 Hz), 6.75 (1H, dd, J=7.8, 0.9Hz), 7.13 (1H, t, J=8.1 Hz), 7.37-7.43 (2H, m), 7.49-7.54 (1H, m),7.71-7.75 (2H, m), 7.83 (1H, dd, J=8.1, 0.9 Hz).

Example 44(1-Ethyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine(56-1)

Magnesium (turning) 246 mg was added to compound (55) in methanol 9 mland the mixture was stirred at room temperature for 3 h. Ice was addedto the reaction mixture which was diluted with chloroform. The insolublematerials were filtered off through cerite and the filtrate wasextracted with chloroform. The extracts were washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue obtained was chromatographed on aluminum oxide inchloroform:hexane (2:1) to give the titled compound as a pale yellow oil97.8 mg. Yield 79%. This was treated with 1 eq. oxalic acid to give thesalt, which was recrystallized from ether-methanol to give colorlesscrystals, m.p. 236-237° C. (dec.).

¹H-NMR(CDCl₃): 1.29 (3H, t, J=7.5 Hz), 2.45 (6H, s), 2.75 (2H, q, J=7.5Hz), 2.86-3.13 (3H, m), 4.12 (1H, dd, J=12.3, 6.3 Hz), 4.54 (1H, d,J=12.3 Hz), 6.59 (1H, dd, J=7.5, 0.9 Hz), 6.91 (1H, dd, J=8.1, 0.9 Hz),6.99 (1H, t, J=7.8 Hz), 7.90 (1H, br s).

Following compounds were obtained, according to the similar treatment.

Compd No R⁷ m.p. ¹H-NMR (CDCl₃) 56-2 vinyl 195-198 2.43 (6H, s),2.64-3.25 (3H, m), 4.12 (dec.) (1H, dd, J=12.0, 6.3 Hz), 4.54 (1H,oxalate dd, J=12.0, 2.1 Hz), 5.27 (1H, d, J=11.4 Hz), 5.43 (1H, d,J=11.4 Hz), 6.58 (1H, dd, J=7.8, 0.9 Hz), 6.79 (1H, dd, J=17.7, 11.4Hz), 6.91 (1H, dd, J=8.1, 0.9 Hz), 7.06 (1H, t, J=8.1 Hz), 8.11 (1H, brs),

Example 45

N-(2,7,8,9-Tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-yl)hydrazinecarboxylicacid tert-butyl ester (57)

t-Butylbuthoxycarbonyl hydrazide 139 mg was added to a solution ofcompound (18-1) 170 mg in dry tetrahydrofuran 6 ml. The mixture wasstirred at room temperature for 4 h and concentrated under reducedpressure. Trifluoroacetic acid 0.7 ml and triethylsilane 212 mg wereadded to the residue. The mixture was stirred for 80 min. 1N-HCl andthen potassium hydroxide pellets were added to the reaction mixture withcooling in ice to alkaline. The mixture was extracted with chloroform.The organic layer was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue obtainedwas chromatographed on aluminum oxide in chloroform:hexane (4:1) to givethe titled compound as crystals, 158 mg (yield 58%). The crudecrystalline materials were recrystallized from hexane-ethyl acetate togive pale yellow crystals, m.p. 171-173° C.(dec.).

¹H-NMR(CDCl₃): 1.46 (9H, s), 2.84-2.93 (1H, m), 3.17-3.24 (2H, m),3.59-3.66 (1H, m), 4.23 (1H, dd, J=12.3, 7.2 Hz), 4.37 (1H, d, J=12.3Hz), 6.21 (1H, br s), 6.61 (1H, d, J=7.5 Hz), 6.96-7.08 (3H, m), 8.11(1H, br s)

Example A

As examples of a compound (I), compounds (I-a) and compounds (I-b) shownin Table 7-28 and Table 29-42, respectively.

TABLE 7 (I-a)

Compd No R⁴ R⁷ R⁸ 1 COOH H H 2 COOMe H H 3 COOEt H H 4 COO-tBu H H 5CONH₂ H H 6 CONHMe H H 7 CONHEt H H 8 CONH-nPr H H 9 CONMe₂ H H 10CONEt₂ H H 11 CON(nPr)₂ H H 12 CONHPh H H 13

H H 14

H H 15

H H 16 NH₂ H H 17 NHMe H H 18 NHEt H H 19 NH-nPr H H 20 NMe₂ H H 21 NEt₂H H 22 N(nPr)₂ H H 23

H H 24

H H 25

H H 26 NHCOMe H H 27 NHCOEt H H

TABLE 8 Compd No R⁴ R⁷ R⁸ 1 NHCO-nPr H H 2 NHCOPh H H 3 NMeCOMe H H 4N(nPr)COMe H H 5 NMeCOPh H H 6 N(nPr)COPh H H 7 NHCOOMe H H 8 NHCOOEt HH 9 NHCOO-tBu H H 10 NHCOOCH₂Ph H H 11 NMeCOOMe H H 12 N(nPr)COOMe H H13 NMeCOOOH₂Ph H H 14 N(nPr)COOCH₂Ph H H 15 NHSO₂Me H H 16 NHSO₂Et H H17 NHSO₂Ph H H 18 NHTs H H 19 NMeSO₂Me H H 20 N(nPr)SO₂Me H H 21NMeSO₂Ph H H 22 N(nPr)SO₂Ph H H 23 COOH Me H 24 COOMe Me H 25 COOEt Et H26 COO-tBu nPr H 27 CONH₂ Me H 28 CONHMe Me H 29 CONHEt Et H 30 CONH-nPrnPr H 31 CONMe₂ Me H 32 CONEt₂ Et H 33 CON(nPr)₂ nPr H 34 CONHPh Me H 35

Me H 36

Et H 37

nPr H 38 NH₂ Me H 39 NHMe Me H 40 NHEt Et H

TABLE 9 Compd No R⁴ R⁷ R⁸ 1 NH-nPr nPr H 2 NMe₂ Me H 3 NEt₂ Et H 4N(nPr)₂ nPr H 5

Me H 6

Et H 7

nPr H 8 NHCOMe Me H 9 NHCOEt Et H 10 NHCO-nPr nPr H 11 NHCOPh Me H 12NMeCOMe Me H 13 N(nPr)COMe Et H 14 NMeCOPh nPr H 15 N(nPr)COPh Me H 16NHCOOMe Me H 17 NHCOOEt Et H 18 NHCOO-tBu nPr H 19 NHCOOCH₂Ph Me H 20NMeCOOMe nPr H 21 N(nPr)COOMe nPr H 22 NMeCOOCH₂Ph Me H 23N(nPr)COOCH₂Ph nPr H 24 NHSO₂Me Me H 25 NHSO₂Et Et H 26 NHSO₂Ph nPr H 27NHTs Et H 28 NMeSO₂Me Me H 29 N(nPr)SO₂Me nPr H 30 NMeSO₂Ph Me H 31N(nPr)SO₂Ph Me H 32 COOH Br H 33 COOMe Br H 34 COOEt CN H 35 COO-tBu BrH 36 CONH₂ Br H 37 CONHMe Br H 38 CONHEt CN H 39 CONHn-Pr Br H 40 CONMe₂Br H 41 CONEt₂ CN H 42 CON(nPr)₂ Br H

TABLE 10 Compd No R⁴ R⁷ R⁸ 1 CONHPh CN H 2

Br H 3

Br H 4

CN H 5 NH₂ Br H 6 NHMe Br H 7 NHEt CN H 8 NH-nPr Br H 9 NMe₂ Br H 10NEt₂ CN H 11 N(nPr)₂ Br H 12

Br H 13

CN H 14

Br H 15 NHCOMe Br H 16 NHCOEt Br H 17 NHCO-nPr CN H 18 NHCOPh Br H 19NMeCOMe Br H 20 N(nPr)COMe Br H 21 NMeCOPh CN H 22 N(nPr)COPh Br H 23NHCOOMe Br H 24 NHCOOEt CN H 25 NHCOO-tBu Br H 26 NHCOOCH₂Ph Br H 27NMeCOOMe CN H 28 N(nPr)COOMe Br H 29 NMeCOOCH₂Ph Br H 30 N(nPr)COOCH₂PhCN H 31 NHSO₂Me Br H 32 NHSO₂Et Br H 33 NHSO₂Ph Br H 34 NHTs CN H 35NMeSO₂Me Br H 36 N(nPr)SO₂Me Br H 37 NMeSO₂Ph Br H 38 N(nPr)SO₂Ph CN H39 COOH Ph H

TABLE 11 Compd No R⁴ R⁷ R⁸ 1 COOMe Ph H 2 COOEt Ph H 3 COO-tBu Ph H 4CONH₂ Ph H 5 CONHMe Ph H 6 CONHEt Ph H 7 CONH-nPr Ph H 8 CONMe₂ Ph H 9CONEt₂ Ph H 10 CON(nPr)₂ Ph H 11 CONHPh Ph H 12

Ph H 13

Ph H 14

Ph H 15 NH₂ Ph H 16 NHMe Ph H 17 NHEt Ph H 18 NH-nPr Ph H 19 NMe₂ Ph H20 NEt₂ Ph H 21 N(nPr)₂ Ph H 22

Ph H 23

Ph H 24

Ph H 25 NHCOMe Ph H 26 NHCOEt Ph H 27 NHCO-nPr Ph H 28 NHCOPh Ph H 29NMeCOMe Ph H 30 N(nPr)COMe Ph H 31 NMeCOPh Ph H 32 N(nPr)COPh Ph H 33NHCOOMe Ph H 34 NHCOOEt Ph H 35 NHCOO-tBu Ph H 36 NHCOOCH₂Ph Ph H 37NMeCOOMe Ph H 38 N(nPr)COOMe Ph H

TABLE 12 Compd No R⁴ R⁷ R⁸ 1 NMeCOOCH₂Ph Ph H 2 N(nPr)COOCH₂Ph Ph H 3NHSO₂Me Ph H 4 NHSO₂Et Ph H 5 NHSO₂Ph Ph H 6 NHTs Ph H 7 NMeSO₂Me Ph H 8N(nPr)SO₂Me Ph H 9 NMeSO₂Ph Ph H 10 N(nPr)SO₂Ph Ph H 11 COOH H Me 12COOMe H Me 13 COOEt H Me 14 COO-tBu H Me 15 CONH₂ H Me 16 CONHMe H Me 17CONHEt H Me 18 CONHn-Pr H Me 19 CONMe₂ H Me 20 CONEt₂ H Me 21 CON(nPr)₂H Me 22 CONHPh H Me 23

H Me 24

H Me 25

H Me 26 NH₂ H Me 27 NHMe H Me 28 NHEt H Me 29 NH-nPr H Me 30 NMe₂ H Me31 NEt₂ H Me 32 N(nPr)₂ H Me 33

H Me 34

H Me 35

H Me 36 NHCOMe H Me 37 NHCOEt H Me

TABLE 13 Compd No R4 R7 R8 1 NHCO-nPr H Me 2 NHCOPh H Me 3 NMeCOMe H Me4 N(nPr)COMe H Me 5 NMeCOPh H Me 6 N(nPr)COPh H Me 7 NHCOOMe H Me 8NHCOOEt H Me 9 NHCOO-tBu H Me 10 NHCOOCH₂Ph H Me 11 NMeCOOMe H Me 12N(nPr)COOMe H Me 13 NMeCOOCH₂Ph H Me 14 N(nPr)COOCH₂Ph H Me 15 NHSO₂Me HMe 16 NHSO₂Et H Me 17 NHSO₂Ph H Me 18 NHTs H Me 19 NMeSO₂Me H Me 20N(nPr)SO₂Me H Me 21 NMeSO₂Ph H Me 22 N(nPr)SO₂Ph H Me 23 COOH Me Me 24COOMe Me Me 25 COOEt Et Me 26 COO-tBu Me Me 27 CONH₂ nPr Me 28 CONHMe MeMe 29 CONHEt Et Me 30 CONH-nPr nPr Me 31 CONMe₂ Me Me 32 CONEt₂ Et Me 33CON(nPr)₂ nPr Me 34 CONHPh Me Me 35

Me Me 36

Et Me 37

nPr Me

TABLE 14 Compd No R⁴ R⁷ R⁸ 1 NH₂ Me Me 2 NHMe Me Me 3 NHEt Me Me 4NH-nPr Et Me 5 NMe₂ Me Me 6 NEt₂ nPr Me 7 N(nPr)₂ nPr Me 8

Me Me 9

Et Me 10

Me Me 11 NHCOMe nPr Me 12 NHCOEt Me Me 13 NHCO-nPr Et Me 14 NHCOPh Me Me15 NMeCOMe nPr Me 16 N(nPr)COMe Me Me 17 NMeCOPh Et Me 18 N(nPr)COPh MeMe 19 NHCOOMe nPr Me 20 NHCOOEt Me Me 21 NHCOO-tBu Et Me 22 NHCOOCH₂PhMe Me 23 NMeCOOMe nPr Me 24 N(nPr)COOMe Me Me 25 NMeCOOCH₂Ph nPr Me 26N(nPr)COOCH₂Ph Me Me 27 NHSO₂Me Et Me 28 NHSO₂Et nPr Me 29 NHSO₂Ph Me Me30 NHTs nPr Me 31 NMeSO₂Me Me Me 32 N(nPr)SO₂Me Et Me 33 NMeSO₂Ph Me Me34 N(nPr)SO₂Ph Et Me 35 COOH Br Me 36 COOMe Br Me 37 COOEt CN Me 38COO-tBu CN Me

TABLE 15 Compd No R⁴ R⁷ R⁸ 1 CONH₂ Br Me 2 CONHMe Br Me 3 CONHEt CN Me 4CONH-nPr Br Me 5 CONMe₂ Br Me 6 CONEt₂ CN Me 7 CON(nPr)₂ Br Me 8 CONHPhCN Me 9

Br Me 10

CN Me 11

Br Me 12 NH₂ Br Me 13 NHMe CN Me 14 NHEt CN Me 15 NH-nPr Br Me 16 NMe₂Br Me 17 NEt₂ CN Me 18 N(nPr)₂ Br Me 19

Br Me 20

CN Me 21

Br Me 22 NHCOMe Br Me 23 NHCOEt Br Me 24 NHCO-nPr CN Me 25 NHCOPh Br Me26 NMeCOMe Br Me 27 N(nPr)COMe CN Me 28 NMeCOPh Br Me 29 N(nPr)COPh BrMe 30 NHCOOMe CN Me 31 NHCOOEt Br Me 32 NHCOO-tBu Br Me 33 NHCOOCH₂Ph BrMe 34 NMeCOOMe CN Me 35 N(nPr)COOMe Br Me

TABLE 16 Compd No R⁴ R⁷ R⁸ 1 NMeCOOCH₂Ph Br Me 2 N(nPr)COOCH₂Ph CN Me 3NHSO₂Me Br Me 4 NHSO₂Et Br Me 5 NHSO2Ph CN Me 6 NHTs Br Me 7 NMeSO₂Me BrMe 8 N(nPr)SO₂Me CN Me 9 NMeSO₂Ph Br Me 10 N(nPr)SO₂Ph Br Me 11 COOH PhMe 12 COOMe Ph Me 13 COOEt Ph Me 14 COO-tBu Ph Me 15 CONH₂ Ph Me 16CONHMe Ph Me 17 CONHEt Ph Me 18 CONH-nPr Ph Me 19 CONMe₂ Ph Me 20 CONEt₂Ph Me 21 CON(nPr)₂ Ph Me 22 CONHPh Ph Me 23

Ph Me 24

Ph Me 25

Ph Me 26 NH₂ Ph Me 27 NHMe Ph Me 28 NHEt Ph Me 29 NH-nPr Ph Me 30 NMe₂Ph Me 31 NEt₂ Ph Me 32 N(nPr)₂ Ph Me 33

Ph Me 34

Ph Me 35

Ph Me

TABLE 17 Compd No R⁴ R⁷ R⁸ 1 NHCOMe Ph Me 2 NHCOEt Ph Me 3 NHCO-nPr PhMe 4 NHCOPh Ph Me 5 NMeCOMe Ph Me 6 N(nPr)COMe Ph Me 7 NMeCOPh Ph Me 8N(nPr)COPh Ph Me 9 NHCOOMe Ph Me 10 NHCOOEt Ph Me 11 NHCOO-tBu Ph Me 12NHCOOCH₂Ph Ph Me 13 NMeCOOMe Ph Me 14 N(nPr)COOMe Ph Me 15 NMeCOOCH₂PhPh Me 16 N(nPr)COOCH₂Ph Ph Me 17 NHSO₂Me Ph Me 18 NHSO₂Et Ph Me 19NHSO₂Ph Ph Me 20 NHTs Ph Me 21 NMeSO₂Me Ph Me 22 N(nPr)SO₂Me Ph Me 23NMeSO₂Ph Ph Me 24 N(nPr)SO₂Ph Ph Me 25 COOH H COPh 26 COOMe H COPh 27COOEt H COPh 28 COO-tBu H COPh 29 CONH₂ H COPh 30 CONHMe H COPh 31CONHEt H COPh 32 CONH-nPr H COPh 33 CONMe₂ H COPh 34 CONEt₂ H COPh 35CON(nPr)₂ H COPh 36 CONHPh H COPh 37

H COPh 38

H COPh 39

H COPh

TABLE 18 Compd No R⁴ R⁷ R⁸ 1 NH₂ H COPh 2 NHMe H COPh 3 NHEt H COPh 4NH-nPr H COPh 5 NMe₂ H COPh 6 NEt₂ H COPh 7 N(nPr)₂ H COPh 8

H COPh 9

H COPh 10

H COPh 11 NHCOMe H COPh 12 NHCOEt H COPh 13 NHCO-nPr H COPh 14 NHCOPh HCOPh 15 NMeCOMe H COPh 16 N(nPr)COMe H COPh 17 NMeCOPh H COPh 18N(nPr)COPh H COPh 19 NHCOOMe H COPh 20 NHCOOEt H COPh 21 NHCOO-tBu HCOPh 22 NHCOOCH₂Ph H COPh 23 NMeCOOMe H COPh 24 N(nPr)COOMe H COPh 25NMeCOOCH₂Ph H COPh 26 N(nPr)COOCH₂Ph H COPh 27 NHSO₂Me H COPh 28 NHSO₂EtH COPh 29 NHSO₂Ph H COPh 30 NHTs H COPh 31 NMeSO₂Me H COPh 32N(nPr)SO₂Me H COPh 33 NMeSO₂Ph H COPh 34 N(nPr)SO₂Ph H COPh 35 COOH MeCOPh 36 COOMe Me COPh 37 COOEt Et COPh 38 COO-tBu nPr COPh 39 CONH₂ MeCOPh

TABLE 19 Compd No R⁴ R⁷ R⁸ 1 CONHMe Et COPh 2 CONHEt nPr COPh 3 CONH-nPrMe COPh 4 CONMe₂ Et COPh 5 CONEt₂ nPr COPh 6 CON(nPr)₂ nPr COPh 7 CONHPhMe COPh 8

nPr COPh 9

Et COPh 10

Me COPh 11 NH₂ Et COPh 12 NHMe Me COPh 13 NHEt Et COPh 14 NH-nPr nPrCOPh 15 NMe₂ Me COPh 16 NEt₂ Et COPh 17 N(nPr)₂ nPr COPh 18

Me COPh 19

Me COPh 20

Me COPh 21 NHCOMe Et COPh 22 NHCOEt Et COPh 23 NHCO-nPr Et COPh 24NHCOPh nPr COPh 25 NMeCOMe nPr COPh 26 N(nPr)COMe nPr COPh 27 NMeCOPh EtCOPh 28 N(nPr)COPh Et COPh 29 NHCOOMe Et COPh 30 NHCOOEt Me COPh 31NHCOO-tBu Me COPh 32 NHCOOCH₂Ph Me COPh 33 NMeCOOMe Et COPh 34N(nPr)COOMe nPr COPh 35 NMeCOOCH₂Ph nPr COPh 36 N(nPr)COOCH₂Ph nPr COPh37 NHSO₂Me Me COPh 38 NHSO₂Et Et COPh

TABLE 20 Compd No R⁴ R⁷ R⁸ 1 NHSO₂Ph nPr COPh 2 NHTs Me COPh 3 NMeSO₂MeEt COPh 4 N(nPr)SO₂Me nPr COPh 5 NMeSO₂Ph Me COPh 6 N(nPr)SO₂Ph Me COPh7 COOH Br COPh 8 COOMe Br COPh 9 COOEt CN COPh 10 COO-tBu Br COPh 11CONH₂ CN COPh 12 CONHMe Br COPh 13 CONHEt CN COPh 14 CONH-nPr Br COPh 15CONMe₂ Br COPh 16 CONEt₂ CN COPh 17 CON(nPr)₂ Br COPh 18 CONHPh Br COPh19

CN COPh 20

Br COPh 21

Br COPh 22 NH₂ CN COPh 23 NHMe Br COPh 24 NHEt CN COPh 25 NH-nPr Br COPh26 NMe₂ Br COPh 27 NEt₂ Br COPh 28 N(nPr)₂ CN COPh 29

Br COPh 30

Br COPh 31

CN COPh 32 NHCOMe Br COPh 33 NHCOEt CN COPh 34 NHCO-nPr Br COPh 35NHCOPh CN COPh 36 NMeCOMe Br COPh 37 N(nPr)COMe CN COPh

TABLE 21 Compd No R⁴ R⁷ R⁸ 1 NMeCOPh CN COPh 2 N(nPr)COPh Br COPh 3NHCOOMe Br COPh 4 NHCOOEt CN COPh 5 NHCOO-tBu Br COPh 6 NHCOOCH₂Ph BrCOPh 7 NMeCOOMe CN COPh 8 N(nPr)COOMe Br COPh 9 NMeCOOCH₂Ph Br COPh 10N(nPr)COOCH₂Ph CN COPh 11 NHSO₂Me Br COPh 12 NHSO₂Et Br COPh 13 NHSO₂PhCN COPh 14 NHTs Br COPh 15 NMeSO₂Me Br COPh 16 N(nPr)SO₂Me CN COPh 17NMeSO2Ph CN COPh 18 N(nPr)SO₂Ph CN COPh 19 COOH Ph COPh 20 COOMe Ph COPh21 COOEt Ph COPh 22 COO-tBu Ph COPh 23 CONH₂ Ph COPh 24 CONHMe Ph COPh25 CONHEt Ph COPh 26 CONH-nPr Ph COPh 27 CONMe₂ Ph COPh 28 CONEt₂ PhCOPh 29 CON(nPr)₂ Ph COPh 30 CONHPh Ph COPh 31

Ph COPh 32

Ph COPh 33

Ph COPh 34 NH₂ Ph COPh 35 NHMe Ph COPh 36 NHEt Ph COPh

TABLE 22 Compd No R⁴ R⁷ R⁸ 1 NH-nPr Ph COPh 2 NMe₂ Ph COPh 3 NEt₂ PhCOPh 4 N(nPr)₂ Ph COPh 5

Ph COPh 6

Ph COPh 7

Ph COPh 8 NHCOMe Ph COPh 9 NHCOEt Ph COPh 10 NHCO-nPr Ph COPh 11 NHCOPhPh COPh 12 NMeCOMe Ph COPh 13 N(nPr)COMe Ph COPh 14 NMeCOPh Ph COPh 15N(nPr)COPh Ph COPh 16 NHCOOMe Ph COPh 17 NHCOOEt Ph COPh 18 NHCOO-tBu PhCOPh 19 NHCOOCH₂Ph Ph COPh 20 NMeCOOMe Ph COPh 21 N(nPr)COOMe Ph COPh 22NMeCOOCH₂Ph Ph COPh 23 N(nPr)COOCH₂Ph Ph COPh 24 NHSO₂Me Ph COPh 25NHSO₂Et Ph COPh 26 NHSO₂Ph Ph COPh 27 NHTs Ph COPh 28 NMeSO₂Me Ph COPh29 N(nPr)SO₂Me Ph COPh 30 NMeSO₂Ph Ph COPh 31 N(nPr)SO₂Ph Ph COPh 32COOH H SO₂Ph 33 COOMe H SO₂Ph 34 COOEt H SO₂Ph 35 COO-tBu H SO₂Ph 36CONH₂ H SO₂Ph 37 CONHMe H SO₂Ph

TABLE 23 Compd No R⁴ R⁷ R⁸ 1 CONHEt H SO₂Ph 2 CONH-nPr H SO₂Ph 3 CONMe₂H SO₂Ph 4 CONEt₂ H SO₂Ph 5 CON(nPr)₂ H SO₂Ph 6 CONHPh H SO₂Ph 7

H SO₂Ph 8

H SO₂Ph 9

H SO₂Ph 10 NH₂ H SO₂Ph 11 NHMe H SO₂Ph 12 NHEt H SO₂Ph 13 NH-nPr H SO₂Ph14 NMe₂ H SO₂Ph 15 NEt₂ H SO₂Ph 16 N(nPr)₂ H SO₂Ph 17

H SO₂Ph 18

H SO₂Ph 19

H SO₂Ph 20 NHCOMe H SO₂Ph 21 NHCOEt H SO₂Ph 22 NHCO-nPr H SO₂Ph 23NHCOPh H SO₂Ph 24 NMeCOMe H SO₂Ph 25 N(nPr)COMe H SO₂Ph 26 NMeCOPh HSO₂Ph 27 N(nPr)COPh H SO₂Ph 28 NHCOOMe H SO₂Ph 29 NHCOOEt H SO₂Ph 30NHCOO-tBu H SO₂Ph 31 NHCOOCH₂Ph H SO₂Ph 32 NMeCOOMe H SO₂Ph 33N(nPr)COOMe H SO₂Ph 34 NMeCOOCH₂Ph H SO₂Ph 35 N(nPr)COOCH₂Ph H SO₂Ph 36NHSO₂Me H SO₂Ph 37 NHSO₂Et H SO₂Ph

TABLE 24 Compd No R⁴ R⁷ R⁸ 1 NHSO₂Ph H SO₂Ph 2 NHTs H SO₂Ph 3 NMeSO₂Me HSO₂Ph 4 N(nPr)SO₂Me H SO₂Ph 5 NMeSO₂Ph H SO₂Ph 6 N(nPr)SO₂Ph H SO₂Ph 7COOH Me SO₂Ph 8 COOMe Me SO₂Ph 9 COOEt Et SO₂Ph 10 COO-tBu nPr SO₂Ph 11CONH₂ Me SO₂Ph 12 CONHMe Me SO₂Ph 13 CONHEt Et SO₂Ph 14 CONH-nPr nPrSO₂Ph 15 CONMe₂ Me SO₂Ph 16 CONEt₂ Me SO₂Ph 17 CON(nPr)₂ Me SO₂Ph 18CONHPh Et SO₂Ph 19

Et SO₂Ph 20

Et SO₂Ph 21

nPr SO₂Ph 22 NH₂ nPr SO₂Ph 23 NHMe nPr SO₂Ph 24 NHEt Et SO₂Ph 25 NH-nPrMe SO₂Ph 26 NMe₂ nPr SO₂Ph 27 NEt₂ Et SO₂Ph 28 N(nPr)₂ Et SO₂Ph 29

Me SO₂Ph 30

Me SO₂Ph 31

Me SO₂Ph 32 NHCOMe Et SO₂Ph 33 NHCOEt Et SO₂Ph 34 NHCO-nPr Et SO₂Ph 35NHCOPh Me SO₂Ph 36 NMeCOMe Me SO₂Ph

TABLE 25 Compd No R⁴ R⁷ R⁸ 1 N(nPr)COMe Me SO₂Ph 2 NMeCOPh nPr SO₂Ph 3N(nPr)COPh nPr SO₂Ph 4 NHCOOMe nPr SO₂Ph 5 NHCOOEt Me SO₂Ph 6 NHCOO-tBuEt SO₂Ph 7 NHCOOCH₂Ph nPr SO₂Ph 8 NMeCOOMe Me SO₂Ph 9 N(nPr)COOMe EtSO₂Ph 10 NMeCOOCH₂Ph nPr SO₂Ph 11 N(nPr)COOCH₂Ph Me SO₂Ph 12 NHSO₂Me EtSO₂Ph 13 NHSO₂Et nPr SO₂Ph 14 NHSO₂Ph Me SO₂Ph 15 NHTs Me SO₂Ph 16NMeSO₂Me Me SO₂Ph 17 N(nPr)SO₂Me nPr SO₂Ph 18 NMeSO₂Ph nPr SO₂Ph 19N(nPr)SO₂Ph nPr SO₂Ph 20 COOH Br SO₂Ph 21 COOMe CN SO₂Ph 22 COOEt BrSO₂Ph 23 COO-tBu CN SO₂Ph 24 CONH² Br SO₂Ph 25 CONHMe Br SO₂Ph 26 CONHEtBr SO₂Ph 27 CONH-nPr Br SO₂Ph 28 CONMe₂ CN SO₂Ph 29 CONEt₂ CN SO₂Ph 30CON(nPr)₂ CN SO₂Ph 31 CONHPh Br SO₂Ph 32

Br SO₂Ph 33

Br SO₂Ph 34

CN SO₂Ph 35 NH₂ Br SO₂Ph 36 NHMe CN SO2Ph

TABLE 26 Compd No R⁴ R⁷ R⁸ 1 NHEt Br SO₂Ph 2 NH-nPr CN SO₂Ph 3 NMe₂ BrSO₂Ph 4 NEt₂ Br SO₂Ph 5 N(nPr)₂ CN SO₂Ph 6

Br SO₂Ph 7

Br SO₂Ph 8

Br SO₂Ph 9 NHCOMe CN SO₂Ph 10 NHCOEt Br SO₂Ph 11 NHCO-nPr CN SO₂Ph 12NHCOPh Br SO₂Ph 13 NMeCOMe Br SO₂Ph 14 N(nPr)COMe CN SO₂Ph 15 NMeCOPh BrSO₂Ph 16 N(nPr)COPh Br SO₂Ph 17 NHCOOMe CN SO₂Ph 18 NHCOOEt Br SO₂Ph 19NHCOO-tBu Br SO₂Ph 20 NHCOOCH₂Ph Br SO₂Ph 21 NMeCOOMe CN SO₂Ph 22N(nPr)COOMe Br SO₂Ph 23 NMeCOOCH₂Ph Br SO₂Ph 24 N(nPr)COOCH₂Ph Br SO₂Ph25 NHSO₂Me CN SO₂Ph 26 NHSO₂Et Br SO₂Ph 27 NHSO₂Ph Br SO₂Ph 28 NHTs CNSO₂Ph 29 NMeSO₂Me Br SO₂Ph 30 N(nPr)SO₂Me Br SO₂Ph 31 NMeSO₂Ph CN SO₂Ph32 N(nPr)SO₂Ph Br SO₂Ph 33 COOH Ph SO₂Ph 34 COOMe Ph SO₂Ph 35 COOEt PhSO₂Ph 36 COO-tBu Ph SO₂Ph 37 CONH₂ Ph SO2Ph

TABLE 27 Compd No R⁴ R⁷ R⁸ 1 CONHMe Ph SO₂Ph 2 CONHEt Ph SO₂Ph 3CONH-nPr Ph SO₂Ph 4 CONMe₂ Ph SO₂Ph 5 CONEt₂ Ph SO₂Ph 6 CON(nPr)₂ PhSO₂Ph 7 CONHPh Ph SO₂Ph 8

Ph SO₂Ph 9

Ph SO₂Ph 10

Ph SO₂Ph 11 NH₂ Ph SO₂Ph 12 NHMe Ph SO₂Ph 13 NHEt Ph SO₂Ph 14 NH-nPr PhSO₂Ph 15 NMe₂ Ph SO₂Ph 16 NEt₂ Ph SO₂Ph 17 N(nPr)₂ Ph SO₂Ph 18

Ph SO₂Ph 19

Ph SO₂Ph 20

Ph SO₂Ph 21 NHCOMe Ph SO₂Ph 22 NHCOEt Ph SO₂Ph 23 NHCO-nPr Ph SO₂Ph 24NHCOPh Ph SO₂Ph 25 NMeCOMe Ph SO₂Ph 26 N(nPr)COMe Ph SO₂Ph 27 NMeCOPh PhSO₂Ph 28 N(nPr)COPh Ph SO₂Ph 29 NHCOOMe Ph SO₂Ph 30 NHCOOEt Ph SO₂Ph 31NHCOO-tBu Ph SO₂Ph 32 NHCOOCH₂Ph Ph SO₂Ph 33 NMeCOOMe Ph SO₂Ph 34N(nPr)COOMe Ph SO₂Ph 35 NMeCOOCH₂Ph Ph SO₂Ph 36 N(nPr)COOCH₂Ph Ph SO2Ph

TABLE 28 Compd No R⁴ R⁷ R⁸ 1 NHSO₂Me Ph SO₂Ph 2 NHSO₂Et Ph SO₂Ph 3NHSO₂Ph Ph SO₂Ph 4 NHTs Ph SO₂Ph 5 NMeSO₂Me Ph SO₂Ph 6 N(nPr)SO₂Me PhSO₂Ph 7 NMeSO₂Ph Ph SO₂Ph 8 N(nPr)SO₂Ph Ph SO₂Ph

TABLE 29 (I-b)

Compd No R⁴ R⁶ R⁷ R⁸ 1 COOH H H H 2 COOMe H H H 3 COOEt H H H 4 COO-tBuH H H 5 CONH₂ H H H 6 CONHMe H H H 7 CONHEt H H H 8 CONH-nPr H H H 9CONMe₂ H H H 10 CONEt₂ H H H 11 CON(nPr)₂ H H H 12 CONHPh H H H 13

H H H 14

H H H 15

H H H 16 NHCOOMe H H H 17 NHCOOEt H H H 18 NHCOO-tBu H H H 19 NHCOOCH₂PhH H H 20 NMeCOOMe H H H 21 N(nPr)COOMe H H H 22 NMeCOOCH₂Ph H H H 23N(nPr)COOCH₂Ph H H H 24 COOH H Me H 25 COOMe H Me H 26 COOEt H Et H

TABLE 30 Compd No R⁴ R⁶ R⁷ R⁸ 1 COO-tBu H nPr H 2 CONH₂ H Me H 3 CONHMeH Me H 4 CONHEt H Et H 5 CONH-nPr H nPr H 6 CONMe₂ H Me H 7 CONEt₂ H MeH 8 CON(nPr)₂ H Me H 9 CONHPh H Et H 10

H Et H 11

H Et H 12

H Et H 13 NHCOOMe H nPr H 14 NHCOOEt H nPr H 15 NHCOO-tBu H nPr H 16NHCOOCH₂Ph H Me H 17 NMeCOOMe H Et H 18 N(nPr)COOMe H nPr H 19NMeCOOCH₂Ph H Me H 20 N(nPr)COOCH₂Ph H nPr H 21 COOH H Br H 22 COOMe HBr H 23 COOEt H CN H 24 COO-tBu H Br H 25 CONH₂ H Br H 26 CONHMe H CN H27 CONHEt H Br H 28 CONH-nPr H CN H 29 CONMe₂ H Br H 30 CONEt₂ H Br H 31CON(nPr)₂ H CN H 32 CONHPh H Br H 33

H Br H 34

H CN H 35

H Br H

TABLE 31 Compd No. R⁴ R⁶ R⁷ R⁸ 1 NHCOOMe H Br H 2 NHCOOEt H CN H 3NHCOO-tBu H Br H 4 NHCOOCH₂Ph H CN H 5 NMeCOOMe H Br H 6 N(nPr)COOMe HCN H 7 NMeCOOCH₂Ph H Br H 8 N(nPr)COOCH₂Ph H CN H 9 COOH H Ph H 10 COOMeH Ph H 11 COOEt H Ph H 12 COO-tBu H Ph H 13 CONH₂ H Ph H 14 CONHMe H PhH 15 CONHEt H Ph H 16 CONH-nPr H Ph H 17 CONMe₂ H Ph H 18 CONEt₂ H Ph H19 CON(nPr)₂ H Ph H 20 CONHPh H Ph H 21

H Ph H 22

H Ph H 23

H Ph H 24 NHCOOMe H Ph H 25 NHCOOEt H Ph H 26 NHCOO-tBu H Ph H 27NHCOOCH₂Ph H Ph H 28 NMeCOOMe H Ph H 29 N(nPr)COOMe H Ph H 30NMeCOOCH₂Ph H Ph H 31 N(nPr)COOCH₂Ph H Ph H 32 COOH H H Me 33 COOMe H HMe 34 COOEt H H Me 35 COO-tBu H H Me 36 CONH₂ H H Me 37 CONHMe H H Me

TABLE 32 Compd No R⁴ R⁶ R⁷ R⁸ 1 CONHEt H H Me 2 CONH-nPr H H Me 3 CONMe₂H H Me 4 CONEt₂ H H Me 5 CON(nPr)₂ H H Me 6 CONHPh H H Me 7

H H Me 8

H H Me 9

H H Me 10 NHCOOMe H H Me 11 NHCOOEt H H Me 12 NHCOO-tBu H H Me 13NHCOOCH₂Ph H H Me 14 NMeCOOMe H H Me 15 N(nPr)COOMe H H Me 16NMeCOOCH₂Ph H H Me 17 N(nPr)COOCH₂Ph H H Me 18 COOH H Me Me 19 COOMe HMe Me 20 COOEt H Et Me 21 COO-tBu H nPr Me 22 CONH₂ H Me Me 23 CONHMe HMe Me 24 CONHEt H Me Me 25 CONH-nPr H Et Me 26 CONMe₂ H Et Me 27 CONEt₂H Et Me 28 CON(nPr)₂ H nPr Me 29 CONHPh H nPr Me 30

H nPr Me 31

H Me Me 32

H Et Me 33 NHCOOMe H nPr Me 34 NHCOOEt H Me Me

TABLE 33 Compd No R⁴ R⁶ R⁷ R⁸ 1 NHCOO-tBu H Et Me 2 NHCOOCH₂Ph H nPr Me3 NMeCOOMe H Me Me 4 N(nPr)COOMe H Me Me 5 NMeCOOCH₂Ph H Et Me 6N(nPr)COOCH₂Ph H nPr Me 7 COOH H Br Me 8 COOMe H CN Me 9 COOEt H Br Me10 COO-tBu H CN Me 11 CONH₂ H Br Me 12 CONHMe H CN Me 13 CONHEt H Br Me14 CONH-nPr H CN Me 15 CONMe₂ H Br Me 16 CONEt₂ H CN Me 17 CON(nPr)₂ HBr Me 18 CONHPh H CN Me 19

H Br Me 20

H Br Me 21

H CN Me 22 NHCOOMe H CN Me 23 NHCOOEt H Br Me 24 NHCOO-tBu H CN Me 25NHCOOCH₂Ph H Br Me 26 NMeCOOMe H Br Me 27 N(nPr)COOMe H CN Me 28NMeCOOCH₂Ph H Br Me 29 N(nPr)COOCH₂Ph H Br Me 30 COOH H Ph Me 31 COOMe HPh Me 32 COOEt H Ph Me 33 COO-tBu H Ph Me 34 CONH₂ H Ph Me 35 CONHMe HPh Me 36 CONHEt H Ph Me 37 CONH-nPr H Ph Me

TABLE 34 Compd No R⁴ R⁶ R⁷ R⁸ 1 CONMe₂ H Ph Me 2 CONEt₂ H Ph Me 3CON(nPr)₂ H Ph Me 4 CONHPh H Ph Me 5

H Ph Me 6

H Ph Me 7

H Ph Me 8 NHCOOMe H Ph Me 9 NHCOOEt H Ph Me 10 NHCOO-tBu H Ph Me 11NHCOOCH₂Ph H Ph Me 12 NMeCOOMe H Ph Me 13 N(nPr)COOMe H Ph Me 14NMeCOOCH₂Ph H Ph Me 15 N(nPr)COOCH₂Ph H Ph Me 16 COOH H H COPh 17 COOMeH H COPh 18 COOEt H H COPh 19 COO-tBu H H COPh 20 CONH₂ H H COPh 21CONHMe H H COPh 22 CONHEt H H COPh 23 CONH-nPr H H COPh 24 CONMe₂ H HCOPh 25 CONEt₂ H H COPh 26 CON(nPr)₂ H H COPh 27 CONHPh H H COPh 28

H H COPh 29

H H COPh 30

H H COPh 31 NHCOOMe H H COPh 32 NHCOOEt H H COPh 33 NHCOO-tBu H H COPh34 NHCOOCH₂Ph H H COPh

TABLE 35 Compd No R⁴ R⁶ R⁷ R⁸ 1 NMeCOOMe H H COPh 2 N(nPr)COOMe H H COPh3 NMeCOOCH₂Ph H H COPh 4 N(nPr)COOCH₂Ph H H COPh 5 COOH H Me COPh 6COOMe H nPr COPh 7 COOEt H Et COPh 8 COO-tBu H Et COPh 9 CONH₂ H Et COPh10 CONHMe H Me COPh 11 CONHEt H Me COPh 12 CONH-nPr H Me COPh 13 CONMe₂H nPr COPh 14 CONEt₂ H nPr COPh 15 CON(nPr)₂ H nPr COPh 16 CONHPh H MeCOPh 17

H Et COPh 18

H nPr COPh 19

H Me COPh 20 NHCOOMe H Me COPh 21 NHCOOEt H Me COPh 22 NHCOO-tBu H EtCOPh 23 NHCOOCH₂Ph H nPr COPh 24 NMeCOOMe H Et COPh 25 N(nPr)COOMe H nPrCOPh 26 NMeCOOCH₂Ph H Me COPh 27 N(nPr)COOCH₂Ph H Me COPh 28 COOH H BrCOPh 29 COOMe H CN COPh 30 COOEt H Br COPh 31 COO-tBu H CN COPh 32 CONH₂H Br COPh 33 CONHMe H Br COPh 34 CONHEt H CN COPh 35 CONH-nPr H CN COPh36 CONMe₂ H Br COPh

TABLE 36 Compd No R⁴ R⁶ R⁷ R⁸  1 CONEt₂ H Br COPh  2 CON(nPr)₂ H Br COPh 3 CONHPh H Br COPh  4

H CN COPh  5

H CN COPh  6

H Br COPh  7 NHCOOMe H CN COPh  8 NHCOOEt H Br COPh  9 NHCOO-tBu H CNCOPh 10 NHCOOCH₂Ph H Br COPh 11 NMeCOOMe H CN COPh 12 N(nPr)COOMe H BrCOPh 13 NMeCOOCH₂Ph H Br COPh 14 N(nPr)COOCH₂Ph H Br COPh 15 COOH H PhCOPh 16 COOMe H Ph COPh 17 COOEt H Ph COPh 18 COO-tBu H Ph COPh 19 CONH₂H Ph COPh 20 CONHMe H Ph COPh 21 CONHEt H Ph COPh 22 CONH-nPr H Ph COPh23 CONMe₂ H Ph COPh 24 CONEt₂ H Ph COPh 25 CON(nPr)₂ H Ph COPh 26 CONHPhH Ph COPh 27

H Ph COPh 28

H Ph COPh 29

H Ph COPh 30 NHCOOMe H Ph COPh 31 NHCOOEt H Ph COPh 32 NHCOO-tBu H PhCOPh

TABLE 37 Compd No R⁴ R⁶ R⁷ R⁸  1 NHCOOCH₂Ph H Ph COPh  2 NMeCOOMe H PhCOPh  3 N(nPr)COOMe H Ph COPh  4 NMeCOOCH₂Ph H Ph COPh  5 N(nPr)COOCH₂PhH Ph COPh  6 COOH H H SO₂Ph  7 COOMe H H SO₂Ph  8 COOEt H H SO₂Ph  9COO-tBu H H SO₂Ph 10 CONH₂ H H SO₂Ph 11 CONHMe H H SO₂Ph 12 CONHEt H HSO₂Ph 13 CONHn-Pr H H SO₂Ph 14 CONMe₂ H H SO₂Ph 15 CONEt₂ H H SO₂Ph 16CON(nPr)₂ H H SO₂Ph 17 CONHPh H H SO₂Ph 18

H H SO₂Ph 19

H H SO₂Ph 20

H H SO₂Ph 21 NHCOOMe H H SO₂Ph 22 NHCOOEt H H SO₂Ph 23 NHCOO-tBu H HSO₂Ph 24 NHCOOCH₂Ph H H SO₂Ph 25 NMeCOOMe H H SO₂Ph 26 N(nPr)COOMe H HSO₂Ph 27 NMeCOOCH₂Ph H H SO₂Ph 28 N(nPr)COOCH₂Ph H H SO₂Ph 29 COOH H MeSO₂Ph 30 COOMe H Et SO₂Ph 31 COOEt H nPr SO₂Ph 32 COO-tBu H Et SO₂Ph 33CONH₂ H nPr SO₂Ph 34 CONHMe H Me SO₂Ph 35 CONHEt H Me SO₂Ph 36 CONH-nPrH nPr SO₂Ph

TABLE 38 Compd No R⁴ R⁶ R⁷ R⁸  1 CONMe₂ H nPr SO₂Ph  2 CONEt₂ H EtSO₂PII  3 CON(nPr)₂ H Et SO₂Ph  4 CONHPh H nPr SO₂Ph  5

H nPr SO₂Ph  6

H nPr SO₂Ph  7

H Me SO₂Ph  8 NHCOOMe H Me SO₂Ph  9 NHCOOEt H Me SO₂Ph 10 NHCOO-tBu H EtSO₂Ph 11 NHCOOCH₂Ph H Et SO₂Ph 12 NMeCOOMe H Et SO₂Ph 13 N(nPr)COOMe HMe SO₂Ph 14 NMeCOOCH₂Ph H Me SO₂Ph 15 N(nPr)COOCH₂Ph H Me SO₂PIi 16 COOHH Br SO₂Ph 17 COOMe H Br SO₂Ph 18 COOEt H Br SO₂Ph 19 COO-tBu H CN SO₂Ph20 CONH₂ H Br SO₂Ph 21 CONHMe H Br SO₂PIi 22 CONHEt H Br SO₂Ph 23CONH-nPr H CN SO₂Ph 24 CONMe₂ H Br SO₂Ph 25 CONEt₂ H Br SO₂Ph 26CON(nPr)₂ H Br SO₂Ph 27 CONHPh H CN SO₂Ph 28

H Br SO₂Ph 29

H Br SO₂Ph 30

H Br SO₂Ph 31 NHCOOMe H Br SO₂Ph 32 NHCOOEt H CN SO₂Ph 33 NHCOO-tBu H BrSO₂Ph

TABLE 39 Compd No R⁴ R⁶ R⁷ R⁸  1 NHCOOCH₂Ph H Br SO₂Ph  2 NMeCOOMe H BrSO₂Ph  3 N(nPr)COOMe H CN SO₂Ph  4 NMeCOOCH₂Ph H Br SO₂Ph  5N(nPr)COOCH₂Ph H Br SO₂Ph  6 COOH H Ph SO₂Ph  7 COOMe H Ph SO₂Ph  8COOEt H Ph SO₂Ph  9 COO-tBu H Ph SO₂Ph 10 CONH₂ H Ph SO₂Ph 11 CONHMe HPh SO₂Ph 12 CONHEt H Ph SO₂Ph 13 CONH-nPr H Ph SO₂Ph 14 CONMe₂ H PhSO₂Ph 15 CONEt₂ H Ph SO₂Ph 16 CON(nPr)₂ H Ph SO₂Ph 17 CONHPh H Ph SO₂Ph18

H Ph SO₂Ph 19

H Ph SO₂Ph 20

H Ph SO₂Ph 21 NHCOOMe H Ph SO₂Ph 22 NHCOOEt H Ph SO₂Ph 23 NHCOO-tBu H PhSO₂Ph 24 NHCOOCH₂Ph H Ph SO₂Ph 25 NMeCOOMe H Ph SO₂Ph 26 N(nPr)COOMe HPh SO₂Ph 27 NMeCOOCH₂Ph H Ph SO₂Ph 28 N(nPr)COOCH₂Ph H Ph SO₂Ph 29 OHCOOMe H H 30 OMe COOMe H H 31 OH COOMe Me H 32 OMe COOMe Me H 33 OHCOOMe Br H 34 OMe COOMe Br H 35 OH COOMe Ph H 36 OMe COOMe Ph H 37 OHCOOMe H Me 38 OMe COOMe H Me

TABLE 40 Comp No R⁴ R⁶ R⁷ R⁸ 1 OH COOMe Me Me 2 OMe COOMe Et Me 3 OHCOOMe Br Me 4 OMe COOMe Br Me 5 OH COOMe Ph Me 6 OMe COOMe Ph Me 7 OHCOOMe H COPh 8 OMe COOMe H COPh 9 OH COOMe Me COPh 10 OMe COOMe nPr COPh11 OH COOMe Br COPh 12 OMe COOMe CN COPh 13 OH COOMe CN COPh 14 OMeCOOMe Ph COPh 15 OH COOMe H SO₂Ph 16 OMe COOMe CN SO₂Ph 17 OH COOMe EtSO₂Ph 18 OMe COOMe Me SO₂Ph 19 OH COOMe CN SO₂Ph 20 OMe COOMe Br SO₂Ph21 OH COOMe Ph SO₂Ph 22 OMe COOMe CN SO₂Ph 23 OH COOEt H H 24 OMe COOEtH H 25 OH COOEt nPr H 26 OMe COOEt Et H 27 OH COOEt Br H 28 OMe COOEt CNH 29 OH COOEt Ph H 30 OMe COOEt CN H 31 OH COOEt H Me 32 OMe COOEt H Me33 OH COOEt nPr Me 34 OMe COOEt CN Me 35 OH COOEt Br Me 36 OMe COOEt CNMe 37 OH COOEt Ph Me 38 OMe COOEt Ph Me 39 OH COOEt H COPh 40 OMe COOEtCN COPh 41 OH COOEt Me COPh

TABLE 41 Comp No R⁴ R⁶ R⁷ R⁸ 1 OMe COOEt Et COPh 2 OH COOEt Br COPh 3OMe COOEt CN COPh 4 OH COOEt Ph COPh 5 OMe COOEt CN COPh 6 OH OQOEt HSO₂Ph 7 OMe OQOEt H SO₂Ph 8 OH COOEt Me SO₂Ph 9 OMe COOEt nPr SO₂Ph 10OH COOEt CN SO₂Ph 11 OMe COOEt Br SO₂Ph 12 OH COOEt Ph SO₂Ph 13 OMeCOOEt Ph SO₂Ph 14 OH CN H H 15 OMe CN CN H 16 OH CN Me H 17 OMe CN Et H18 OH CN Br H 19 OMe CN CN H 20 OH CN Ph H 21 OMe CN Ph H 22 OH CN H Me23 OMe CN H Me 24 OH CN CN Me 25 OMe CN Me Me 26 OH CN Br Me 27 OMe CNBr Me 28 OH CN Ph Me 29 OMe CN CN Me 30 OH CN H COPh 31 OMe CN H COPh 32OH CN CN COPh 33 OMe CN Et COPh 34 OH CN Br COPh 35 OMe CN Br COPh 36 OHCN Ph COPh 37 OMe CN CN COPh 38 OH CN H SO₂Ph 39 OMe CN H SO₂Ph 40 OH CNnPr SO₂Ph 41 OMe CN nPr SO₂Ph

TABLE 42 Comp No R⁴ R⁶ R⁷ R⁸ 1 OH CN Br SO₂Ph 2 OMe CN Br SO₂Ph 3 OH CNCN SO₂Ph 4 OMe CN Ph SO₂Ph 5 OH CH₂NH₂ H H 6 OMe CH₂NH₂ H H 7 OH CH₂NH₂nPr H 8 OMe CH₂NH₂ Me H 9 OH CH₂NH₂ Br H 10 OMe CH₂NH₂ CN H 11 OH CH₂NH₂Ph H 12 OMe CH₂NH₂ Ph H 13 OH CH₂NH₂ CN Me 14 OMe CH₂NH₂ H Me 15 OHCH₂NH₂ Et Me 16 OMe CH₂NH₂ CN Me 17 OH CH₂NH₂ Br Me 18 OMe CH₂NH₂ Br Me19 OH CH₂NH₂ Ph Me 20 OMe CH₂NH₂ CN Me 21 OH CH₂NH₂ H COPh 22 OMe CH₂NH₂H COPh 23 OH CH₂NH₂ nPr COPh 24 OMe CH₂NH₂ nPr COPh 25 OH CH₂NH₂ Br COPh26 OMe CH₂NH₂ Br COPh 27 OH CH₂NH₂ Ph COPh 28 OMe CH₂NH₂ Ph COPh 29 OHCH₂NH₂ H SO₂Ph 30 OMe CH₂NH₂ H SO₂Ph 31 OH CH₂NH₂ Me SO₂Ph 32 OMe CH₂NH₂Me SO₂Ph 33 OH CH₂NH₂ CN SO₂Ph 34 OMe CH₂NH₂ Br SO₂Ph 35 OH CH₂NH₂ CNSO₂Ph 36 OMe CH₂NH₂ Ph SO₂Ph

EXPERIMENTALS

A mixture of radioactive ligands and some cardinal numbers of testcompounds was incubated with a sample of cell membrane, which wasprepared from brain of rats or HEK293 cells, which expressed thereceptor, under the following conditions. Then, the sample was filteredby suction on a Whatman GF/C. Radioactivity on the filter wasencountered by the use of a liquid scintillation counter. 50% Inhibitoryconcentration values (IC₅₀ values) of each selective binding werecalculated for test compounds and the Ki value was obtained by applyingan equation of Cheng-Prusoff [Biochem. Pharmacol. 22 (1973) 3099-3108]Ki=IC₅₀/(1+[L]/Kd). [L] represents a concentration of the radio ligandused and Kd shows dissociation constant.

TABLE 43 Condition of Receptor Origin Radioactive Ligand Incubation5-HT1A Rat 1 nM [³H] 8-OH- 25° C. 30 min hippocampus DPAT 5-HT2 Ratcerebral 1 nM [³H] Ketanserin 37° C. 30 min cortex 5-HT6 rat5-HT₆ 8 nM[³H] 5HT 25° C. 120 min (HEK293) 4 nM [³H] LSD 37° C. 60 min 5-HT7 Human5-HT₇ 0.5 nM [³H] 5CT 25° C. 120 min (HEK293)

TABLE 44 Ki value (nM) ±SE Example Compd. No. 5-HT1A 5-HT6 5-HT7 5 8-136 12 19-1  81 12 19-2  23 97 12 19-3  5.7 46 12 19-5  10 12 19-7  19 1219-10 2.5 12 19-15 7.7 4.6 16 12 19-16 58 62 86 12 19-18 2.7 12 19-193.8 13 20-1  1.7 13 20-5  0.49 13 20-6  2.7 13 20-9  86 78 13 20-10 9545 13 20-11 5.7 13 20-12 2.7 13 20-13 3.9 13 20-14 22 13 20-15 29 1320-16 22 13 20-17 29 13 20-18 22 13 20-19 12 13 20-20 11 13 20-21 2.7 1320-22 26 13 20-23 9.9 13 20-24 3.2 13 20-25 36 14 21 14 24 36-1  29 6524 36-2  8.5 24 36-3  58 4.2 24 36-4  26 38 83 22 27 39 27 73 28 40 1532 74 29 41 57 34 46-2  34 46-3  18 34 46-1  28 35 47 78 36 48 1

INDUSTRIAL APPLICABILITY

Having an affinity against serotonin receptors, compounds described inthis invention are useful as medicines such as therapeutic agents ofdiseases for central nervous systems thereof. Furthermore, thesecompounds are useful as synthetic intermediates thereof.

1. A compound, prodrug, pharmaceutically acceptable salt or solvatethereof of the formula:

wherein R¹ is hydrogen; R² is hydrogen or lower alkyl; R³ is hydrogen;R⁴ is —COOR¹³ wherein R¹³ is hydrogen or ester moiety; R⁵ is hydrogen,or R³ and R⁵ taken together may form a bond; R⁶ is hydrogen; R⁷ ishydrogen, halogen, optionally substituted lower alkyl, cycloalkyl, orcycloalkyl(lower)alkyl; R⁸ is hydrogen, optionally substituted loweralkyl, cycloalkyl, or cycloalkyl(lower)alkyl; and R⁹, R¹⁰ and R¹¹ areeach independently hydrogen, halogen, optionally substituted loweralkyl, cycloalkyl, or cycloalkyl(lower)alkyl.
 2. A compound, prodrug,pharmaceutically acceptable salt or solvate thereof, according to claim1, wherein R² is hydrogen.
 3. A compound, prodrug, pharmaceuticallyacceptable salt or solvate thereof, according to claim 1, wherein R³ ishydrogen.
 4. A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to claim 1, wherein R⁵ is hydrogen.
 5. Acompound, prodrug, pharmaceutically acceptable salt or solvate thereof,according to claim 1, wherein R³ and R⁵ taken together may form a bond.6. A compound, prodrug, pharmaceutically acceptable salt or solvatethereof, according to claim 1, wherein R⁴ represents —COOR¹³ wherein R¹³is hydrogen or lower alkyl.
 7. A compound, prodrug, pharmaceuticallyacceptable salt or solvate thereof, according to claim 1, wherein R⁴ is—COOR¹³ wherein R¹³ is hydrogen or methyl.
 8. A compound, prodrug,pharmaceutically acceptable salt or solvate thereof, according to claim1, wherein R⁷ is hydrogen, lower alkyl, or halogen.
 9. A compound,prodrug, pharmaceutically acceptable salt or solvate thereof, accordingto claim 1, wherein R⁷ is hydrogen, methyl, ethyl, or halogen.
 10. Acompound, prodrug, pharmaceutically acceptable salt or solvate thereof,according to claim 1, wherein R⁸ is hydrogen, or optionally substitutedlower alkyl.
 11. A compound, prodrug, pharmaceutically acceptable saltor solvate thereof, according to claim 1, wherein R⁸ is hydrogen.
 12. Acompound, prodrug, pharmaceutically acceptable salt or solvate thereof,according to claim 1, wherein all of R⁹, R¹⁰ and R¹¹ are hydrogen.
 13. Acompound, prodrug, pharmaceutically acceptable salt or solvate thereof,according to claim 1, wherein R² is hydrogen, R³ and R⁵ are hydrogen ortaken together may form a bond.
 14. A compound, prodrug,pharmaceutically acceptable salt or solvate thereof, according to claim1, wherein all of R⁹, R¹⁰ and R¹¹ are hydrogen; wherein R² is hydrogen;wherein R³ and R⁵ are hydrogen or together form a bond; wherein R⁶ ishydrogen; R⁷ is hydrogen, lower alkyl, or halogen and R⁸ is hydrogen, orlower alkyl.
 15. A compound, prodrug, pharmaceutically acceptable saltor solvate thereof, according to claim 1, wherein R⁹ is hydrogen orhalogen.
 16. A compound, prodrug, pharmaceutically acceptable salt orsolvate thereof, according to claim 1, wherein R⁹ is hydrogen.
 17. Acompound, prodrug, pharmaceutically acceptable salt or solvate thereof,according to claim 1, wherein R¹⁰ is hydrogen.
 18. A compound, prodrug,pharmaceutically acceptable salt or solvate thereof, according to claim1, wherein R¹¹ is hydrogen, halogen, or lower alkyl.
 19. A compound,prodrug, pharmaceutically acceptable salt or solvate thereof, accordingto claim 1, wherein R¹¹ is hydrogen, halogen, or methyl.
 20. A compound,prodrug, pharmaceutically acceptable salt or solvate thereof, accordingto claim 1, wherein R¹, R², R³, R⁵, R⁶, R⁹, and R¹⁰ is hydrogen; R⁷ ishydrogen, halogen, or lower alkyl, R⁸ is hydrogen and R¹¹ is hydrogen,halogen, or lower alkyl.
 21. A pharmaceutical composition comprising acompound, prodrug, pharmaceutically acceptable salt or solvate thereofaccording to claim 1, together with a pharmaceutically acceptableadditive thereof.
 22. A method for preparing a therapeutic orprophylactic medicament for a serotonin receptor mediated disease, whichcomprises mixing a compound, prodrug, pharmaceutically acceptable saltor solvate thereof according to claim 1, together with apharmaceutically acceptable additive thereof.